Skip to main content

The Adrenergic System in Cardiovascular Metabolism and Aging

  • Chapter
  • First Online:
The Cardiovascular Adrenergic System
  • 784 Accesses

Abstract

The adrenergic nervous system plays a crucial role in cardiovascular physiology. Adrenergic receptors, which are extensively distributed throughout the body, essentially mediate cellular communication, allowing cells to sense external signals or to talk each other via neurotransmitters and hormones. These receptors are involved in a plethora of pathophysiological processes and a large amount of studies has demonstrated their participation in cardiovascular metabolism and aging.

This chapter represents an updated and systematic appraisal of the literature in this field, summarizing the major findings of research investigating the functional role of neuroendocrine adrenergic system in regulating cardiovascular aging and cardiovascular metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol. 1948;153:586–600.

    CAS  PubMed  Google Scholar 

  2. Anis Y, Leshem O, Reuveni H, Wexler I, Ben Sasson R, Yahalom B, Laster M, Raz I, Ben Sasson S, Shafrir E, Ziv E. Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes. Diabetologia. 2004;47:1232–44.

    CAS  PubMed  Google Scholar 

  3. Ashrafian H, Neubauer S. Metabolic modulation in heart failure: high time for a definitive clinical trial. Heart. 2011;97:267–8.

    PubMed  Google Scholar 

  4. Avendano MS, Lucas E, Jurado-Pueyo M, Martinez-Revelles S, Vila-Bedmar R, Mayor F Jr, Salaices M, Briones AM, Murga C. Increased nitric oxide bioavailability in adult GRK2 hemizygous mice protects against angiotensin II-induced hypertension. Hypertension. 2014;63:369–75.

    CAS  PubMed  Google Scholar 

  5. Azevedo PS, Minicucci MF, Santos PP, Paiva SA, Zornoff LA. Energy metabolism in cardiac remodeling and heart failure. Cardiol Rev. 2013;21:135–40.

    PubMed  Google Scholar 

  6. Balaban RS. Perspectives on: SGP symposium on mitochondrial physiology and medicine: metabolic homeostasis of the heart. J Gen Physiol. 2012;139:407–14.

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Barbato E, Berger A, Delrue L, Van Durme F, Manoharan G, Boussy T, Heyndrickx GR, De Bruyne B, Ciampi Q, Vanderheyden M, Wijns W, Bartunek J. GLU-27 variant of beta2-adrenergic receptor polymorphisms is an independent risk factor for coronary atherosclerotic disease. Atherosclerosis. 2007;194:e80–6.

    CAS  PubMed  Google Scholar 

  8. Becker TA, DellaValle B, Gesser H, Rodnick KJ. Limited effects of exogenous glucose during severe hypoxia and a lack of hypoxia-stimulated glucose uptake in isolated rainbow trout cardiac muscle. J Exp Biol. 2013;216:3422–32.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Begum N, Shen W, Manganiello V. Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility. Curr Opin Pharmacol. 2011;11:725–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Belge C, Hammond J, Dubois-Deruy E, Manoury B, Hamelet J, Beauloye C, Markl A, Pouleur AC, Bertrand L, Esfahani H, Jnaoui K, Gotz KR, Nikolaev VO, Vanderper A, Herijgers P, Lobysheva I, Iaccarino G, Hilfiker-Kleiner D, Tavernier G, Langin D, Dessy C, Balligand JL. Enhanced expression of beta3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation. 2014;129:451–62.

    CAS  PubMed  Google Scholar 

  11. Boettger T, Beetz N, Kostin S, Schneider J, Kruger M, Hein L, Braun T. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J Clin Invest. 2009;119:2634–47.

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Boriani G, Diemberger I, Martignani C, Biffi M, Branzi A. The epidemiological burden of atrial fibrillation: a challenge for clinicians and health care systems. Eur Heart J. 2006;27:893–4.

    PubMed  Google Scholar 

  13. Borkowski KR, Gros R, Schneider H. Vascular beta-adrenoceptor-mediated responses in hypertension and ageing in rats. J Auton Pharmacol. 1992;12:389–401.

    CAS  PubMed  Google Scholar 

  14. Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, Laurent S. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension. 2002;39:10–5.

    CAS  PubMed  Google Scholar 

  15. Boyda HN, Procyshyn RM, Pang CC, Barr AM. Peripheral adrenoceptors: the impetus behind glucose dysregulation and insulin resistance. J Neuroendocrinol. 2013;25:217–28.

    CAS  PubMed  Google Scholar 

  16. Bruck H, Leineweber K, Park J, Weber M, Heusch G, Philipp T, Brodde OE. Human beta2-adrenergic receptor gene haplotypes and venodilation in vivo. Clin Pharmacol Ther. 2005;78:232–8.

    CAS  PubMed  Google Scholar 

  17. Buemann B, Toubro S, Astrup A. Effects of the two beta3-agonists, ZD7114 and ZD2079 on 24 hour energy expenditure and respiratory quotient in obese subjects. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of. Obesity. 2000;24:1553–60.

    CAS  Google Scholar 

  18. Burger D, Kwart DG, Montezano AC, Read NC, Kennedy CR, Thompson CS, Touyz RM. Microparticles induce cell cycle arrest through redox-sensitive processes in endothelial cells: implications in vascular senescence. J Am Heart Assoc. 2012;1:e001842.

    PubMed Central  PubMed  Google Scholar 

  19. Camici P, Marraccini P, Lorenzoni R, Ferrannini E, Buzzigoli G, Marzilli M, L’Abbate A. Metabolic markers of stress-induced myocardial ischemia. Circulation. 1991;83:III8–13.

    CAS  PubMed  Google Scholar 

  20. Carobbio S, Hagen RM, Lelliott CJ, Slawik M, Medina-Gomez G, Tan CY, Sicard A, Atherton HJ, Barbarroja N, Bjursell M, Bohlooly YM, Virtue S, Tuthill A, Lefai E, Laville M, Wu T, Considine RV, Vidal H, Langin D, Oresic M, Tinahones FJ, Fernandez-Real JM, Griffin JL, Sethi JK, Lopez M, Vidal-Puig A. Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity. Diabetes. 2013;62:3697–708.

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Cesetti T, Hernandez-Guijo JM, Baldelli P, Carabelli V, Carbone E. Opposite action of beta1- and beta2-adrenergic receptors on Ca(V)1 L-channel current in rat adrenal chromaffin cells. J Neurosci. 2003;23:73–83.

    CAS  PubMed  Google Scholar 

  22. Chen M, Sato PY, Chuprun JK, Peroutka RJ, Otis NJ, Ibetti J, Pan S, Sheu SS, Gao E, Koch WJ. Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targeting. Circ Res. 2013;112:1121–34.

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Chess DJ, Stanley WC. Role of diet and fuel overabundance in the development and progression of heart failure. Cardiovasc Res. 2008;79:269–78.

    CAS  PubMed  Google Scholar 

  24. Chideckel EW, Goodner CJ, Koerker DJ, Johnson DG, Ensinck JW. Role of glucagon in mediating metabolic effects of epinephrine. Am J Physiol. 1977;232:E464–70.

    CAS  PubMed  Google Scholar 

  25. Christensen NJ, Jensen EW. Sympathoadrenal activity and psychosocial stress. The significance of aging, long-term smoking, and stress models. Ann N Y Acad Sci. 1995;771:640–7.

    CAS  PubMed  Google Scholar 

  26. Ciccarelli M, Santulli G, Campanile A, Galasso G, Cervero P, Altobelli GG, Cimini V, Pastore L, Piscione F, Trimarco B, Iaccarino G. Endothelial alpha1-adrenoceptors regulate neo-angiogenesis. Br J Pharmacol. 2008;153:936–46.

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Ciccarelli M, Chuprun JK, Rengo G, Gao E, Wei Z, Peroutka RJ, Gold JI, Gumpert A, Chen M, Otis NJ, Dorn GW, 2nd, Trimarco, B., Iaccarino G, Koch WJ. G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia. Circulation. 2011;123:1953–62.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Ciccarelli M, Santulli G, Pascale V, Trimarco B, Iaccarino G. Adrenergic receptors and metabolism: role in development of cardiovascular disease. Front Physiol. 2013;4:265.

    PubMed Central  PubMed  Google Scholar 

  29. Ciccarelli M, Rusciano MR, Sorriento D, Basilicata F, Santulli G, Campiglia P, Bertamino A, De Luca N, Trimarco B, Iaccarino G, Illario M. CaMKII protects MKP-1 from proteasome degradation in endothelial cells. Cell Signal. 2014;10:2167–74.

    Google Scholar 

  30. Cipolletta E, Campanile A, Santulli G, Sanzari E, Leosco D, Campiglia P, Trimarco B, Iaccarino G. The G protein coupled receptor kinase 2 plays an essential role in beta-adrenergic receptor-induced insulin resistance. Cardiovasc Res. 2009;84:407–15.

    CAS  PubMed  Google Scholar 

  31. Cockcroft JR, Gazis AG, Cross DJ, Wheatley A, Dewar J, Hall IP, Noon JP. Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension. 2000;36:371–5.

    CAS  PubMed  Google Scholar 

  32. Collins S, Cao W, Robidoux J. Learning new tricks from old dogs: beta-adrenergic receptors teach new lessons on firing up adipose tissue metabolism. Mol Endocrinol. 2004;18:2123–31.

    CAS  PubMed  Google Scholar 

  33. Cordero-Reyes AM, Gupte AA, Youker KA, Loebe M, Hsueh WA, Torre-Amione G, Taegtmeyer H, Hamilton DJ. Freshly isolated mitochondria from failing human hearts exhibit preserved respiratory function. J Mol Cell Cardiol. 2014;68:98–105.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Cortez V, Santana M, Marques AP, Mota A, Rosmaninho-Salgado J, Cavadas C. Regulation of catecholamine release in human adrenal chromaffin cells by beta-adrenoceptors. Neurochem Int. 2012;60:387–93.

    CAS  PubMed  Google Scholar 

  35. D’Ascia SL, D’Ascia C, Marino V, Lombardi A, Santulli R, Chiariello M, Santulli G. Cardiac resynchronisation therapy response predicts occurrence of atrial fibrillation in non-ischaemic dilated cardiomyopathy. Int J Clin Pract. 2011;65:1149–55.

    PubMed  Google Scholar 

  36. Davinelli S, Willcox DC, Scapagnini G. Extending healthy ageing: nutrient sensitive pathway and centenarian population. Immun Ageing. 2012;9:9.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. DeBosch B, Sambandam N, Weinheimer C, Courtois M, Muslin AJ. Akt2 regulates cardiac metabolism and cardiomyocyte survival. J Biol Chem. 2006;281:32841–51.

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Degos V, Peineau S, Nijboer C, Kaindl AM, Sigaut S, Favrais G, Plaisant F, Teissier N, Gouadon E, Lombet A, Saliba E, Collingridge GL, Maze M, Nicoletti F, Heijnen C, Mantz J, Kavelaars A, Gressens P. G protein-coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation-induced sensitization to excitotoxic neurodegeneration. Ann Neurol. 2013;73:667–78.

    CAS  PubMed  Google Scholar 

  39. Dehvari N, Hutchinson DS, Nevzorova J, Dallner OS, Sato M, Kocan M, Merlin J, Evans BA, Summers RJ, Bengtsson T. beta(2)-Adrenoceptors increase translocation of GLUT4 via GPCR kinase sites in the receptor C-terminal tail. Br J Pharmacol. 2012;165:1442–56.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Deibert DC, DeFronzo RA. Epinephrine-induced insulin resistance in man. J Clin Invest. 1980;65:717–21.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Deo SH, Jenkins NT, Padilla J, Parrish AR, Fadel PJ. Norepinephrine increases NADPH oxidase-derived superoxide in human peripheral blood mononuclear cells via alpha-adrenergic receptors. Am J Physiol Regul Integr Comp Physiol. 2013;305:R1124–R32.

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Des Rosiers C, Labarthe F, Lloyd SG, Chatham JC. Cardiac anaplerosis in health and disease: food for thought. Cardiovasc Res. 2011;90:210–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Dias P, Terracciano CM. Hyperpolarization-activated cyclic nucleotide-gated channels and ventricular arrhythmias in heart failure: a novel target for therapy? J Am Heart Assoc. 2013;2:e000287.

    PubMed Central  PubMed  Google Scholar 

  44. Dinenno FA, Tanaka H, Stauffer BL, Seals DR. Reductions in basal limb blood flow and vascular conductance with human ageing: role for augmented alpha-adrenergic vasoconstriction. J Physiol. 2001;536:977–83.

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Docherty JR. Subtypes of functional alpha1-adrenoceptor. Cell Mol Life Sci. 2010;67:405–17.

    CAS  PubMed  Google Scholar 

  46. Donato AJ. Ageing and vascular adrenoceptor desensitization: too little, too late? J Physiol. 2007;582:9–10.

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Drake MT, Shenoy SK, Lefkowitz RJ. Trafficking of G protein-coupled receptors. Circ Res. 2006;99:570–82.

    CAS  PubMed  Google Scholar 

  48. Santulli G, Iaccarino G, De Luca N, Trimarco B, Condorelli G. Atrial fibrillation and microRNAs. Front Physiol. 2014;5:15.

    CAS  PubMed  Google Scholar 

  49. Evron T, Daigle TL, Caron MG. GRK2: multiple roles beyond G protein-coupled receptor desensitization. Trends Pharmacol Sci. 2012;33:154–64.

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Fleg JL, Strait J. Age-associated changes in cardiovascular structure and function: a fertile milieu for future disease. Heart Fail Rev. 2012 17:545–54.

    PubMed  Google Scholar 

  51. Foucart S, de Champlain J, Nadeau R. In vivo interactions between prejunctional alpha 2- and beta 2-adrenoceptors at the level of the adrenal medulla. Can J Physiol Pharmacol. 1988;66:1340–3.

    CAS  PubMed  Google Scholar 

  52. Fu X, Koller S, Abd Alla J, Quitterer U. Inhibition of G-protein-coupled receptor kinase 2 (GRK2) triggers the growth-promoting mitogen-activated protein kinase (MAPK) pathway. J Biol Chem. 2013a;288:7738–55.

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Fu Y, Westenbroek RE, Scheuer T, Catterall WA. Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response. Proc Natl Acad Sci USA. 2013b;110:19621–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Fu Q, Xu B, Liu Y, Parikh D, Li J, Li Y, Zhang Y, Riehle C, Zhu Y, Rawlings T, Shi Q, Clark RB, Chen X, Abel ED, Xiang YK. Insulin inhibits cardiac contractility by inducing a Gi-biased beta2 adrenergic signaling in hearts. Diabetes. 2014;8:2676–89.

    Google Scholar 

  55. Fusco A, Santulli G, Sorriento D, Cipolletta E, Garbi C, Dorn GW, 2nd, Trimarco, B., Feliciello A, Iaccarino G. Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis. Cell Signal. 2012;24:468–75.

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Galvao TF, Khairallah RJ, Dabkowski ER, Brown BH, Hecker PA, O’Connell KA, O’Shea KM, Sabbah HN, Rastogi S, Daneault C, Des Rosiers C, Stanley WC. Marine n3 polyunsaturated fatty acids enhance resistance to mitochondrial permeability transition in heart failure but do not improve survival. Am J Physiol Heart Circ Physiol. 2013;304:H12–H21.

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Garcia-Guerra L, Nieto-Vazquez I, Vila-Bedmar R, Jurado-Pueyo M, Zalba G, Diez J, Murga C, Fernandez-Veledo S, Mayor F Jr, Lorenzo M. G protein-coupled receptor kinase 2 plays a relevant role in insulin resistance and obesity. Diabetes. 2010;59:2407–17.

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Garcia-Guerra L, Vila-Bedmar R, Carrasco-Rando M, Cruces-Sande M, Martin M, Ruiz-Gomez A, Ruiz-Gomez M, Lorenzo M, Fernandez-Veledo S, Mayor F Jr, Murga C, Nieto-Vazquez I. Skeletal muscle myogenesis is regulated by G protein-coupled receptor kinase 2. J Mol Cell Biol. 2014;6:299–311.

    CAS  PubMed  Google Scholar 

  59. Gartner F, Seidel T, Schulz U, Gummert J, Milting H. Desensitization and internalization of endothelin receptor A: impact of G protein-coupled receptor kinase 2 (GRK2)-mediated phosphorylation. J Biol Chem. 2013;288:32138–48.

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Gatto F, Feelders R, van der Pas R, Kros JM, Dogan F, van Koetsveld PM, van der Lelij AJ, Neggers SJ, Minuto F, de Herder W, Lamberts SW, Ferone D, Hofland LJ. beta-Arrestin 1 and 2 and G protein-coupled receptor kinase 2 expression in pituitary adenomas: role in the regulation of response to somatostatin analogue treatment in patients with acromegaly. Endocrinology. 2013;154:4715–25.

    CAS  PubMed  Google Scholar 

  61. Gauthier C, Rozec B, Manoury B, Balligand JL. Beta-3 adrenoceptors as new therapeutic targets for cardiovascular pathologies. Curr Heart Fail Rep. 2011;8:184–92.

    CAS  PubMed  Google Scholar 

  62. Georgescu A, Pluteanu F, Flonta ML, Badila E, Dorobantu M, Popov D. Nebivolol induces a hyperpolarizing effect on smooth muscle cells in the mouse renal artery by activation of beta-2-adrenoceptors. Pharmacology. 2008;81:110–7.

    CAS  PubMed  Google Scholar 

  63. Glatz JF, Luiken JJ, Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol Rev. 2010;90:367–417.

    CAS  PubMed  Google Scholar 

  64. Gopal DM, Kommineni M, Ayalon N, Koelbl C, Ayalon R, Biolo A, Dember LM, Downing J, Siwik DA, Liang CS, Colucci WS. Relationship of plasma galectin-3 to renal function in patients with heart failure: effects of clinical status, pathophysiology of heart failure, and presence or absence of heart failure. J Am Heart Assoc. 2012;1:e000760.

    PubMed Central  PubMed  Google Scholar 

  65. Gros R, Benovic JL, Tan CM, Feldman RD. G-protein-coupled receptor kinase activity is increased in hypertension. J Clin Invest. 1997;99:2087–93.

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Gurdal H, Friedman E, Johnson MD. Beta-adrenoceptor-G alpha S coupling decreases with age in rat aorta. Mol Pharmacol. 1995;47:772–8.

    CAS  PubMed  Google Scholar 

  67. Hajjar I, Zhao P, Alsop D, Novak V. Hypertension and cerebral vasoreactivity: a continuous arterial spin labeling magnetic resonance imaging study. Hypertension. 2010;56:859–64.

    PubMed Central  CAS  PubMed  Google Scholar 

  68. Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ. The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange. Nature. 1998;392:626–30.

    CAS  PubMed  Google Scholar 

  69. Harris DM, Cohn HI, Pesant S, Eckhart AD. GPCR signalling in hypertension: role of GRKs. Clin Sci (Lond). 2008;115:79–89.

    CAS  Google Scholar 

  70. He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature. 2012;481:511–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Heinonen I, Wendelin-Saarenhovi M, Kaskinoro K, Knuuti J, Scheinin M, Kalliokoski KK. Inhibition of alpha-adrenergic tone disturbs the distribution of blood flow in the exercising human limb. Am J Physiol Heart Circ Physiol. 2013;305:H163–H72.

    CAS  PubMed  Google Scholar 

  72. Hogikyan RV, Supiano MA. Arterial alpha-adrenergic responsiveness is decreased and SNS activity is increased in older humans. Am J Physiol. 1994;266:E717–E24.

    CAS  PubMed  Google Scholar 

  73. Hudsmith LE, Neubauer S. Detection of myocardial disorders by magnetic resonance spectroscopy. Nat Clin Pract Cardiovasc Med. 2008;5(Suppl 2):S49–56.

    CAS  PubMed  Google Scholar 

  74. Hudsmith LE, Neubauer S. Magnetic resonance spectroscopy in myocardial disease. JACC Cardiovasc Imaging. 2009;2:87–96.

    PubMed  Google Scholar 

  75. Iaccarino G, Keys JR, Rapacciuolo A, Shotwell KF, Lefkowitz RJ, Rockman HA, Koch WJ. Regulation of myocardial betaARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing alpha1B-adrenergic receptors. J Am Coll Cardiol. 2001;38:534–40.

    CAS  PubMed  Google Scholar 

  76. Iaccarino G, Lefkowitz RJ, Koch WJ. Myocardial G protein-coupled receptor kinases: implications for heart failure therapy. Proc Assoc Am Physicians. 1999;111:399–405.

    CAS  PubMed  Google Scholar 

  77. Iaccarino G, Ciccarelli M, Sorriento D, Cipolletta E, Cerullo V, Iovino GL, Paudice A, Elia A, Santulli G, Campanile A, Arcucci O, Pastore L, Salvatore F, Condorelli G, Trimarco B. AKT participates in endothelial dysfunction in hypertension. Circulation. 2004;109:2587–93.

    CAS  PubMed  Google Scholar 

  78. Iaccarino G, Ciccarelli M, Sorriento D, Galasso G, Campanile A, Santulli G, Cipolletta E, Cerullo V, Cimini V, Altobelli GG, Piscione F, Priante O, Pastore L, Chiariello M, Salvatore F, Koch WJ, Trimarco B. Ischemic neoangiogenesis enhanced by beta2-adrenergic receptor overexpression: a novel role for the endothelial adrenergic system. Circ Res. 2005;97:1182–9.

    CAS  PubMed  Google Scholar 

  79. Izzo R, Cipolletta E, Ciccarelli M, Campanile A, Santulli G, Palumbo G, Vasta A, Formisano S, Trimarco B, Iaccarino G. Enhanced GRK2 expression and desensitization of betaAR vasodilatation in hypertensive patients. Clin Transl Sci. 2008;1:215–20.

    CAS  PubMed  Google Scholar 

  80. Jansen AS, Nguyen XV, Karpitskiy V, Mettenleiter TC, Loewy AD. Central command neurons of the sympathetic nervous system: basis of the fight-or-flight response. Science. 1995;270:644–6.

    CAS  PubMed  Google Scholar 

  81. Kang KB, Rajanayagam MA, van der Zypp A, Majewski H. A role for cyclooxygenase in aging-related changes of beta-adrenoceptor-mediated relaxation in rat aortas. Naunyn Schmiedebergs Arch Pharmacol. 2007;375:273–81.

    CAS  PubMed  Google Scholar 

  82. Kashihara T, Hirose M, Shimojo H, Nakada T, Gomi S, Hongo M, Yamada M. beta(2)-Adrenergic and M(2)-muscarinic receptors decrease basal t-tubular L-type Ca2+ channel activity and suppress ventricular contractility in heart failure. Eur J Pharmacol. 2014;724:122–31.

    CAS  PubMed  Google Scholar 

  83. Kaya AI, Onaran HO, Ozcan G, Ambrosio C, Costa T, Balli S, Ugur O. Cell contact-dependent functional selectivity of beta2-adrenergic receptor ligands in stimulating cAMP accumulation and extracellular signal-regulated kinase phosphorylation. J Biol Chem. 2012;287:6362–74.

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Kenakin T, Agnati LF, Caron M, Fredholm B, Guidoli D, Kobilka B, Lefkowitz RW, Lohse M, Woods A, Fuxe K. International Workshop at the Nobel Forum, Karolinska Institutet on G protein-coupled receptors: finding the words to describe monomers, oligomers, and their molecular mechanisms and defining their meaning. Can a consensus be reached? J Recept Signal Transduct Res. 2010;30:284–6.

    CAS  PubMed  Google Scholar 

  85. Khalaila JM, Elami A, Caraco Y. Interaction between beta2 adrenergic receptor polymorphisms determines the extent of isoproterenol-induced vasodilatation ex vivo. Pharmacogenet Genomics. 2007;17:803–11.

    CAS  PubMed  Google Scholar 

  86. Kobilka BK, Dixon RA, Frielle T, Dohlman HG, Bolanowski MA, Sigal IS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ. cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci USA. 1987;84:46–50.

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Kollias A, Stergiou GS, Dolan E, O’Brien E. Ambulatory arterial stiffness index: a systematic review and meta-analysis. Atherosclerosis. 2012;224:291–301.

    CAS  PubMed  Google Scholar 

  88. Kunnas T, Lahtio R, Kortelainen ML, Kalela A, Nikkari ST. Gln27Glu variant of Beta2-adrenoceptor gene affects male type fat accumulation in women. Lipids Health Dis. 2009;8:43.

    PubMed Central  PubMed  Google Scholar 

  89. Lachance V, Cartier A, Genier S, Munger S, Germain P, Labrecque P, Parent JL. Regulation of beta2-adrenergic receptor maturation and anterograde trafficking by an interaction with Rab geranylgeranyltransferase: modulation of Rab geranylgeranylation by the receptor. J Biol Chem. 2011;286:40802–13.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Wronska A, Kurkowska-Jastrzebska I, Santulli G. Application of microRNAs in diagnosis and treatment of cardiovascular disease. Acta Physiol (Oxf). 2015;213(1):60–83.

    CAS  PubMed  Google Scholar 

  91. Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging. Circulation. 2003;107:490–7.

    PubMed  Google Scholar 

  92. Lam CS, Lyass A, Kraigher-Krainer E, Massaro JM, Lee DS, Ho JE, Levy D, Redfield MM, Pieske BM, Benjamin EJ, Vasan RS. Cardiac dysfunction and noncardiac dysfunction as precursors of heart failure with reduced and preserved ejection fraction in the community. Circulation. 2011;124:24–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Lampri E, Ioachim E. Angiogenesis: something old, something new. Angiogenesis: insight from a systematic overview. Hauppauge: (Edited by Gaetano Santulli)—Nova Science. 2013, pp. 1–30.

    Google Scholar 

  94. Lanni F, Santulli G, Izzo R, Rubattu S, Zanda B, Volpe M, Iaccarino G, Trimarco B. The Pl(A1/A2) polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients. J Hypertens. 2007;25:551–6.

    CAS  PubMed  Google Scholar 

  95. Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, Astrup A. Effect of a 28-d treatment with L-796568, a novel beta(3)-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr. 2002;76:780–8.

    CAS  PubMed  Google Scholar 

  96. Lavi S, Nevo O, Thaler I, Rosenfeld R, Dayan L, Hirshoren N, Gepstein L, Jacob G. Effect of aging on the cardiovascular regulatory systems in healthy women. Am J Physiol Regul Integr Comp Physiol. 2007;292:R788–R93.

    CAS  PubMed  Google Scholar 

  97. Lefkowitz RJ. A tale of two callings. J Clin Invest. 2011;121:4201–3.

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Lefkowitz RJ. An interview with Robert J. Lefkowitz. Trends Pharmacol Sci. 2012;33:51–2.

    PubMed  Google Scholar 

  99. Lembo G, Napoli R, Capaldo B, Rendina V, Iaccarino G, Volpe M, Trimarco B, Sacca L. Abnormal sympathetic overactivity evoked by insulin in the skeletal muscle of patients with essential hypertension. J Clin Invest. 1992;90:24–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Lembo G, Iaccarino G, Vecchione C, Barbato E, Izzo R, Fontana D, Trimarco B. Insulin modulation of an endothelial nitric oxide component present in the alpha2- and beta-adrenergic responses in human forearm. J Clin Invest. 1997a;100:2007–14.

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Lembo G, Iaccarino G, Vecchione C, Barbato E, Morisco C, Monti F, Parrella L, Trimarco B. Insulin enhances endothelial alpha2-adrenergic vasorelaxation by a pertussis toxin mechanism. Hypertension. 1997b;30:1128–34.

    CAS  PubMed  Google Scholar 

  102. Leone TC, Kelly DP. Transcriptional control of cardiac fuel metabolism and mitochondrial function. Cold Spring Harb Symp Quant Biol. 2011;76:175–82.

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Li H, Ma XQ, Ye F, Zhang J, Zhou X, Wang ZH, Li YM, Zhang GY. Expressions of cardiac sympathetic norepinephrine transporter and beta1-adrenergic receptor decreased in aged rats. J Zhejiang Univ Sci B. 2009;10:203–10.

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Li YF, Shi ST. Age-dependent differential crosstalk between alpha(1)-adrenergic and angiotensin receptors. Can J Cardiol. 2009;25:481–5.

    PubMed Central  PubMed  Google Scholar 

  105. Liggett SB. Polymorphisms of the beta2-adrenergic receptor. N Engl J Med. 2002;346:536–8.

    CAS  PubMed  Google Scholar 

  106. Ling S, Nanhwan M, Qian J, Kodakandla M, Castillo AC, Thomas B, Liu H, Ye Y. Modulation of microRNAs in hypertension-induced arterial remodeling through the beta1 and beta3-adrenoreceptor pathways. J Mol Cell Cardiol. 2013;65:127–36.

    CAS  PubMed  Google Scholar 

  107. Lopaschuk GD, Kelly DP. Signalling in cardiac metabolism. Cardiovasc Res. 2008;79:205–7.

    CAS  PubMed  Google Scholar 

  108. Lucidi P, Rossetti P, Porcellati F, Pampanelli S, Candeloro P, Andreoli AM, Perriello G, Bolli GB, Fanelli CG. Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: the role of lipolysis. Diabetes. 2010;59:1349–57.

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Lupien JR, Hirshman MF, Horton ES. Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness. Am J Physiol. 1990;259:E210–5.

    CAS  PubMed  Google Scholar 

  110. Lymperopoulos A. Ischemic emergency?: endothelial cells have their own "adrenaline shot" at hand. Hypertension. 2012;60:12–4.

    CAS  PubMed  Google Scholar 

  111. Lymperopoulos A. Physiology and pharmacology of the cardiovascular adrenergic system. Front Physiol. 2013;4:240.

    PubMed Central  PubMed  Google Scholar 

  112. Lymperopoulos A, Bathgate A. Pharmacogenomics of the heptahelical receptor regulators G-protein-coupled receptor kinases and arrestins: the known and the unknown. Pharmacogenomics. 2012;13:323–41.

    CAS  PubMed  Google Scholar 

  113. Lymperopoulos A, Negussie S, Walklett K. beta1- and alpha2C-adrenergic receptor polymorphisms and the antiarrhythmic effect of bucindolol in heart failure with reduced ejection fraction. Pharmacogenomics. 2013;14:1545–9.

    CAS  PubMed  Google Scholar 

  114. Lyon AR, Nikolaev VO, Miragoli M, Sikkel MB, Paur H, Benard L, Hulot JS, Kohlbrenner E, Hajjar RJ, Peters NS, Korchev YE, Macleod KT, Harding SE, Gorelik J. Plasticity of surface structures and beta(2)-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure. Circ Heart Fail. 2012;5:357–65.

    CAS  PubMed  Google Scholar 

  115. Ma Y, Krueger JJ, Redmon SN, Uppuganti S, Nyman JS, Hahn MK, Elefteriou F. Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis. J Biol Chem. 2013;288:30105–13.

    PubMed Central  CAS  PubMed  Google Scholar 

  116. Masuo K, Rakugi H, Ogihara T, Lambert GW. Different mechanisms in weight loss-induced blood pressure reduction between a calorie-restricted diet and exercise. Hypertension research : official journal of the Japanese Society of. Hypertension. 2012;35:41–7.

    CAS  Google Scholar 

  117. Mayor F Jr, Lucas E, Jurado-Pueyo M, Garcia-Guerra L, Nieto-Vazquez I, Vila-Bedmar R, Fernandez-Veledo S, Murga C. G Protein-coupled receptor kinase 2 (GRK2): A novel modulator of insulin resistance. Arch Physiol Biochem. 2011;117:125–30.

    CAS  PubMed  Google Scholar 

  118. McGarrigle D, Huang XY.GPCRs signaling directly through Src-family kinases. Sci STKE. 2007;2007:pe35.

    PubMed  Google Scholar 

  119. Mei Y, Yin N, Jin X, He J, Yin Z. The regulatory role of the adrenergic agonists phenylephrine and isoproterenol on fetal hemoglobin expression and erythroid differentiation. Endocrinology. 2013;154:4640–9.

    CAS  PubMed  Google Scholar 

  120. Milan A, Tosello F, Fabbri A, Vairo A, Leone D, Chiarlo M, Covella M, Veglio F. Arterial stiffness: from physiology to clinical implications. High blood pressure & cardiovascular prevention : the official journal of the Italian Society of. Hypertension. 2011;18:1–12.

    Google Scholar 

  121. Monahan KD, Feehan RP, Sinoway LI, Gao Z. Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing. J Physiol. 2013;591:2937–47.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Montesanto A, Dato S, Bellizzi D, Rose G, Passarino G. Epidemiological, genetic and epigenetic aspects of the research on healthy ageing and longevity. Immun Ageing. 2012;9:6.

    PubMed Central  PubMed  Google Scholar 

  123. Nakaya M, Tajima M, Kosako H, Nakaya T, Hashimoto A, Watari K, Nishihara H, Ohba M, Komiya S, Tani N, Nishida M, Taniguchi H, Sato Y, Matsumoto M, Tsuda M, Kuroda M, Inoue K, Kurose H. GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance. Nat Commun. 2013;4:1532.

    PubMed Central  PubMed  Google Scholar 

  124. Neglia D, De Caterina A, Marraccini P, Natali A, Ciardetti M, Vecoli C, Gastaldelli A, Ciociaro D, Pellegrini P, Testa R, Menichetti L, L’Abbate A, Stanley WC, Recchia FA. Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2007;293:H3270–8.

    CAS  PubMed  Google Scholar 

  125. Neubauer S. The failing heart–an engine out of fuel. N Engl J Med. 2007;356:1140–51.

    PubMed  Google Scholar 

  126. Ngala RA, O’Dowd J, Wang SJ, Agarwal A, Stocker C, Cawthorne MA, Arch JR. Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and beta2-adrenoceptor mechanisms. Br J Pharmacol. 2008;155:395–406.

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J. Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science. 2010;327:1653–7.

    CAS  PubMed  Google Scholar 

  128. Nishida M, Sato Y, Nakaya M, Kurose H. Regulation of cardiac hypertrophy by the formation of G protein-coupled receptor–TRPC channel protein complex. Nihon Yakurigaku Zasshi. 2009;134:131–6.

    CAS  PubMed  Google Scholar 

  129. Nygaard R, Zou Y, Dror RO, Mildorf TJ, Arlow DH, Manglik A, Pan AC, Liu CW, Fung JJ, Bokoch MP, Thian FS, Kobilka TS, Shaw DE, Mueller L, Prosser RS, Kobilka BK. The Dynamic Process of beta(2)-Adrenergic Receptor Activation. Cell. 2013;152:532–42.

    PubMed Central  CAS  PubMed  Google Scholar 

  130. O’Connor SW, Scarpace PJ, Abrass IB. Age-associated decrease of adenylate cyclase activity in rat myocardium. Mech Ageing Dev. 1981;16:91–5.

    PubMed  Google Scholar 

  131. Olivetti G, Giordano G, Corradi D, Melissari M, Lagrasta C, Gambert SR, Anversa P. Gender differences and aging: effects on the human heart. J Am Coll Cardiol. 1995;26:1068–79.

    CAS  PubMed  Google Scholar 

  132. Oriente F, Iovino S, Cassese A, Romano C, Miele C, Troncone G, Balletta M, Perfetti A, Santulli G, Iaccarino G, Valentino R, Beguinot F, Formisano P. Overproduction of phosphoprotein enriched in diabetes (PED) induces mesangial expansion and upregulates protein kinase C-beta activity and TGF-beta1 expression. Diabetologia. 2009;52:2642–52.

    CAS  PubMed  Google Scholar 

  133. Parati G, Esler M. The human sympathetic nervous system: its relevance in hypertension and heart failure. Eur Heart J. 2012;33:1058–66.

    CAS  PubMed  Google Scholar 

  134. Penela P, Ribas C, Mayor F, Jr. Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cell Signal. 2003;15:973–81.

    CAS  PubMed  Google Scholar 

  135. Penela P, Nogues L, Mayor F, Jr. Role of G protein-coupled receptor kinases in cell migration. Curr Opin Cell Biol. 2014;27:10–7.

    CAS  PubMed  Google Scholar 

  136. Phillips D, Ten Hove M, Schneider JE, Wu CO, Sebag-Montefiore L, Aponte AM, Lygate CA, Wallis J, Clarke K, Watkins H, Balaban RS, Neubauer S. Mice over-expressing the myocardial creatine transporter develop progressive heart failure and show decreased glycolytic capacity. J Mol Cell Cardiol. 2010;48:582–90.

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Prasad A, Popovic ZB, Arbab-Zadeh A, Fu Q, Palmer D, Dijk E, Greenberg NL, Garcia MJ, Thomas JD, Levine BD. The effects of aging and physical activity on Doppler measures of diastolic function. Am J Cardiol. 2007;99:1629–36.

    PubMed Central  PubMed  Google Scholar 

  138. Puri R, Liew GY, Nicholls SJ, Nelson AJ, Leong DP, Carbone A, Copus B, Wong DT, Beltrame JF, Worthley SG, Worthley MI. Coronary beta2-adrenoreceptors mediate endothelium-dependent vasoreactivity in humans: novel insights from an in vivo intravascular ultrasound study. Eur Heart J. 2012;33:495–504.

    CAS  PubMed  Google Scholar 

  139. Quinones MJ, Nicholas SB, Lyon CJ. Insulin resistance and the endothelium. Curr Diabetes Rep. 2005 5, 246–53.

    CAS  Google Scholar 

  140. Reiter E, Ahn S, Shukla AK, Lefkowitz RJ. Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol. 2012;52:179–97.

    PubMed Central  CAS  PubMed  Google Scholar 

  141. Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ. Severe hypoglycemia-induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes. 2013;62:3570–81.

    PubMed Central  CAS  PubMed  Google Scholar 

  142. Rezaee M, Penta K, Quertermous T. Del1 mediates VSMC adhesion, migration, and proliferation through interaction with integrin alpha(v)beta(3). Am J Physiol Heart Circ Physiol. 2002;282:H1924–H32.

    CAS  PubMed  Google Scholar 

  143. Robinson JD, Pitcher JA. G protein-coupled receptor kinase 2 (GRK2) is a Rho-activated scaffold protein for the ERK MAP kinase cascade. Cell Signal. 2013;25:2831–9.

    CAS  PubMed  Google Scholar 

  144. Rosca MG, Hoppel CL. Mitochondria in heart failure. Cardiovasc Res. 2010;88:40–50.

    PubMed Central  CAS  PubMed  Google Scholar 

  145. Roth BL, Marshall FH. NOBEL 2012 Chemistry: Studies of a ubiquitous receptor family. Nature. 2012;492:57.

    CAS  PubMed  Google Scholar 

  146. Roth Flach RJ, Matevossian A, Akie TE, Negrin KA, Paul MT, Czech MP. beta3-Adrenergic receptor stimulation induces E-selectin-mediated adipose tissue inflammation. J Biol Chem. 2013;288:2882–92.

    PubMed Central  CAS  PubMed  Google Scholar 

  147. Ruuskanen JO, Laurila J, Xhaard H, Rantanen VV, Vuoriluoto K, Wurster S, Marjamaki A, Vainio M, Johnson MS, Scheinin M. Conserved structural, pharmacological and functional properties among the three human and five zebrafish alpha 2-adrenoceptors. Br J Pharmacol. 2005;144:165–77.

    PubMed Central  CAS  PubMed  Google Scholar 

  148. Santulli G. Coronary heart disease risk factors and mortality. JAMA. 2012a;307:1137.

    CAS  PubMed  Google Scholar 

  149. Santulli G. Thrombolysis outcomes in acute ischemic stroke patients with prior stroke and diabetes mellitus. Neurology. 2012b;78:840.

    PubMed  Google Scholar 

  150. Santulli G. Epidemiology of cardiovascular disease in the 21st century: updated numbers and updated facts. J Cardiovasc Dis. 2013;1:1–2.

    Google Scholar 

  151. Santulli G. Adrenal signaling in heart failure: something more than a distant ship’s smoke on the horizon. Hypertension. 2014;63:215–6.

    CAS  PubMed  Google Scholar 

  152. Santulli G, Iaccarino G. Pinpointing beta adrenergic receptor in ageing pathophysiology: victim or executioner? Evidence from crime scenes. Immun Ageing. 2013;10:10.

    PubMed Central  PubMed  Google Scholar 

  153. Santulli G, Totary-Jain H. Tailoring mTOR-based therapy: molecular evidence and clinical challenges. Pharmacogenomics. 2013;14:1517–26.

    PubMed Central  CAS  PubMed  Google Scholar 

  154. Santulli G, Cipolletta E, Sorriento D, Del Giudice C, Anastasio A, Monaco S, Maione AS, Condorelli G, Puca A, Trimarco B, Illario M, Iaccarino G. CaMK4 Gene Deletion Induces Hypertension. J Am Heart Assoc. 2012a;1:e001081.

    PubMed Central  PubMed  Google Scholar 

  155. Santulli G, D’Ascia S, D’Ascia C. Regarding the impact of left ventricular size on response to cardiac resynchronization therapy. Am Heart J. 2012b;163:e11.

    PubMed  Google Scholar 

  156. Santulli G, D’Ascia S L, D’Ascia C. Development of atrial fibrillation in recipients of cardiac resynchronization therapy: the role of atrial reverse remodelling. Can J Cardiol. 2012c;28(245):e217.

    Google Scholar 

  157. Santulli G, Lombardi A, Sorriento D, Anastasio A, Del Giudice C, Formisano P, Beguinot F, Trimarco B, Miele C, Iaccarino G. Age-related impairment in insulin release: the essential role of beta(2)-adrenergic receptor. Diabetes. 2012d;61:692–701.

    CAS  Google Scholar 

  158. Santulli G, Ciccarelli M, Trimarco B, Iaccarino G. Physical activity ameliorates cardiovascular health in elderly subjects: the functional role of the beta adrenergic system. Front Physiol. 2013a;4:209.

    PubMed Central  PubMed  Google Scholar 

  159. Santulli G, Trimarco B, Iaccarino G. G-Protein-Coupled receptor Kinase 2 and hypertension: molecular insights and pathophysiological mechanisms. High Blood Press Cardiovasc Prev. 2013b;20:5–12

    CAS  PubMed  Google Scholar 

  160. Sorriento D, Ciccarelli M, Santulli G, Illario M, Trimarco B, Iaccarino G. Trafficking GRK2: cellular and metabolic consequences of GRK2 subcellular localization. Transl Med UniSa. 2014;10:3–7.

    CAS  Google Scholar 

  161. Santulli G, Wronska A, Uryu K, Diacovo T, Gao M, Marx S, Kitajewski J, Chilton J, Akat K, Tuschl T, Marks AR, Totary-Jain H. A microRNA-based strategy to selectively inhibit restenosis while preserving endothelial function. J Clin Invest. 2014;124(9):4102–14.

    Google Scholar 

  162. Sardu C, Marfella R, Santulli G. Impact of diabetes mellitus on the clinical response to cardiac resynchronization therapy in elderly people. J Cardiovasc Transl Res. 2014;7:362–8.

    PubMed  Google Scholar 

  163. Sardu C, Marfella R, Santulli G, Paolisso G. Functional role of microRNA in cardiac resynchronization therapy outcome. Pharmacogenomics. 2014;15(8):1159–68.

    Google Scholar 

  164. Sardu C, Carreras G, Katsanos S, Kamperidis V, Pace MC, Passavanti MB, Fava I, Paolisso P, Pieretti G, Nicoletti GF, Santulli G, Paolisso G, Marfella R. Metabolic syndrome is associated with a poor outcome in patients affected by outflow tract premature ventricular contractions treated by catheter ablation. BMC Cardiovasc Disord. 2014;14(1):176.

    Google Scholar 

  165. Scarpace PJ, Armbrecht HJ. Adenylate cyclase in senescence: catecholamine and parathyroid hormone pathways. Rev Clini Basic Pharmacol. 1987;6:105–18.

    CAS  Google Scholar 

  166. Schernthaner G. Pleiotropic effects of thiazolidinediones on traditional and non-traditional atherosclerotic risk factors. Int J Clin Pract. 2009;63:912–29.

    CAS  PubMed  Google Scholar 

  167. Santulli G. Angiopoietin-like proteins: a comprehensive look. Front Endocrinol. 2014;5:4.

    CAS  PubMed  Google Scholar 

  168. Schwarz K, Siddiqi N, Singh S, Neil CJ, Dawson DK, Frenneaux MP. The breathing heart - mitochondrial respiratory chain dysfunction in cardiac disease. Int J Cardiol. 2014;171:134–43.

    PubMed  Google Scholar 

  169. Seals DR, Dinenno FA. Collateral damage: cardiovascular consequences of chronic sympathetic activation with human aging. Am J Physiol Heart Circ Physiol. 2004;287:H1895–H905.

    CAS  PubMed  Google Scholar 

  170. Seals DR, Esler MD. Human ageing and the sympathoadrenal system. J Physiol. 2000;528:407–17.

    PubMed Central  CAS  PubMed  Google Scholar 

  171. Shimizu I, Minamino T, Toko H, Okada S, Ikeda H, Yasuda N, Tateno K, Moriya J, Yokoyama M, Nojima A, Koh GY, Akazawa H, Shiojima I, Kahn CR, Abel ED, Komuro I. Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. J Clin Invest. 2010;120:1506–14.

    PubMed Central  CAS  PubMed  Google Scholar 

  172. Singh M, Moniri NH. Reactive oxygen species are required for beta2 adrenergic receptor-beta-arrestin interactions and signaling to ERK1/2. Biochem Pharmacol. 2012;84:661–9.

    CAS  PubMed  Google Scholar 

  173. Smith EG, Voyles WF, Kirby BS, Markwald RR, Dinenno FA. Ageing and leg postjunctional alpha-adrenergic vasoconstrictor responsiveness in healthy men. J Physiol. 2007;582:63–71.

    PubMed Central  CAS  PubMed  Google Scholar 

  174. Sonkusare SK, Bonev AD, Ledoux J, Liedtke W, Kotlikoff MI, Heppner TJ, Hill-Eubanks DC, Nelson MT. Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science. 2012;336:597–601.

    PubMed Central  CAS  PubMed  Google Scholar 

  175. Sorond FA, Galica A, Serrador JM, Kiely DK, Iloputaife I, Cupples LA, Lipsitz LA. Cerebrovascular hemodynamics, gait, and falls in an elderly population: MOBILIZE Boston Study. Neurology. 2010;74:1627–33.

    PubMed Central  CAS  PubMed  Google Scholar 

  176. Sorriento D, Santulli G, Fusco A, Anastasio A, Trimarco B, Iaccarino G. Intracardiac injection of AdGRK5-NT reduces left ventricular hypertrophy by inhibiting NF-kappaB-dependent hypertrophic gene expression. Hypertension. 2010;56:696–704.

    CAS  PubMed  Google Scholar 

  177. Matarese A, Santulli G. Angiogenesis in chronic obstructive pulmonary disease: a translational appraisal. Transl Med UniSa. 2012;3:49-56.

    Google Scholar 

  178. Sorriento D, Santulli G, Del Giudice C, Anastasio A, Trimarco B, Iaccarino G. Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo. Hypertension. 2012b ;60(1):129–36.

    CAS  PubMed  Google Scholar 

  179. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P, Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Revi. 2011;27(7):639–53.

    Google Scholar 

  180. Stein CM, Nelson R, Deegan R, He H, Wood M, Wood AJ. Forearm beta adrenergic receptor-mediated vasodilation is impaired, without alteration of forearm norepinephrine spillover, in borderline hypertension. J Clin Invest. 1995;96:579–85.

    PubMed Central  CAS  PubMed  Google Scholar 

  181. Stessman J, Eliakim R, Cahan C, Ebstein RP. Deterioration of beta-receptor-adenylate cyclase function in elderly, hospitalized patients. J Gerontol. 1984;39:667–72.

    CAS  PubMed  Google Scholar 

  182. Straznicky NE, Lambert EA, Nestel PJ, McGrane MT, Dawood T, Schlaich MP, Masuo K, Eikelis N, de Courten B, Mariani JA, Esler MD, Socratous F, Chopra R, Sari CI, Paul E, Lambert GW. Sympathetic neural adaptation to hypocaloric diet with or without exercise training in obese metabolic syndrome subjects. Diabetes. 2010;59:71–9.

    PubMed Central  PubMed  Google Scholar 

  183. Straznicky NE, Eikelis N, Nestel PJ, Dixon JB, Dawood T, Grima MT, Sari CI, Schlaich MP, Esler MD, Tilbrook AJ, Lambert GW, Lambert EA. Baseline sympathetic nervous system activity predicts dietary weight loss in obese metabolic syndrome subjects. J Clin Endocrinol Metab. 2012a;97:605–13.

    CAS  PubMed  Google Scholar 

  184. Straznicky NE, Grima MT, Sari CI, Eikelis N, Lambert EA, Nestel PJ, Esler MD, Dixon JB, Chopra R, Tilbrook AJ, Schlaich MP, Lambert GW. Neuroadrenergic dysfunction along the diabetes continuum: a comparative study in obese metabolic syndrome subjects. Diabetes. 2012b;61:2506–16.

    PubMed Central  CAS  PubMed  Google Scholar 

  185. Sun Y, Huang J, Xiang Y, Bastepe M, Juppner H, Kobilka BK, Zhang JJ, Huang XY. Dosage-dependent switch from G protein-coupled to G protein-independent signaling by a GPCR. EMBO J. 2007a;26:53–64.

    PubMed Central  PubMed  Google Scholar 

  186. Sun Y, McGarrigle D, Huang XY. When a G protein-coupled receptor does not couple to a G protein. Mol Biosyst. 2007b;3:849–54.

    CAS  PubMed  Google Scholar 

  187. Sun X, Icli B, Wara AK, Belkin N, He S, Kobzik L, Hunninghake GM, Vera MP, Blackwell TS, Baron RM, Feinberg MW. MicroRNA-181b regulates NF-kappaB-mediated vascular inflammation. J Clin Invest. 2012;122:1973–90.

    PubMed Central  CAS  PubMed  Google Scholar 

  188. Szepietowska B, Zhu W, Czyzyk J, Eid T, Sherwin RS. EphA5-EphrinA5 interactions within the ventromedial hypothalamus influence counterregulatory hormone release and local glutamine/glutamate balance during hypoglycemia. Diabetes. 2013;62:1282–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  189. Taegtmeyer H. Tracing cardiac metabolism in vivo: one substrate at a time. J Nucl Med. 2010;51(Suppl 1):80S-7S.

    Google Scholar 

  190. Taguchi K, Sakata K, Ohashi W, Imaizumi T, Imura J, Hattori Y. Tonic inhibition by G protein-coupled receptor kinase 2 of Akt/endothelial nitric-oxide synthase signaling in human vascular endothelial cells under conditions of hyperglycemia with high insulin levels. J Pharmacol Exp Ther. 2014;349:199–208.

    PubMed  Google Scholar 

  191. ter Laan M, van Dijk JM, Elting JW, Staal MJ, Absalom AR. Sympathetic regulation of cerebral blood flow in humans: a review. Br J Anaesth. 2013;111:361–7.

    CAS  PubMed  Google Scholar 

  192. Trimarco B. Modern clinical management of arterial hypertension: fixed or free combination therapies? Foreword. High blood pressure & cardiovascular prevention : the official journal of the Italian Society of. Hypertension. 2011;18(Suppl 1):1–2.

    Google Scholar 

  193. Umanskaya A, Santulli G, Xie W, Andersson DC, Reiken SR, Marks AR. Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging. Proc Natl Acad Sci U S A. 2014;111(42):15250–5.

    Google Scholar 

  194. van Brummelen P, Buhler FR, Kiowski W, Amann FW. Age-related decrease in cardiac and peripheral vascular responsiveness to isoprenaline: studies in normal subjects. Clin Sci (Lond). 1981;60:571–7.

    Google Scholar 

  195. Vasudevan NT, Mohan ML, Gupta MK, Martelli EE, Hussain AK, Qin Y, Chandrasekharan UM, Young D, Feldman AM, Sen S, Dorn GW 2nd, Dicorleto PE, Naga Prasad SV. Gbetagamma-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor alpha-induced cardiac beta-adrenergic receptor dysfunction. Circulation. 2013;128:377–87.

    CAS  PubMed  Google Scholar 

  196. Vestal RE, Wood AJ, Shand DG. Reduced beta-adrenoceptor sensitivity in the elderly. Clin Pharmacol Ther. 1979;26:181–6.

    CAS  PubMed  Google Scholar 

  197. Vicco MH, Pujato N, Bontempi I, Rodeles L, Marcipar I, Bottasso OA. beta1-Selective Adrenoceptor Antagonists Increase Plasma Levels of Anti-p2beta Antibodies and Decrease Cardiac Involvement in Chronic Progressive Chagas Heart Disease. Can J Cardiol. 2014;30:332–7.

    PubMed  Google Scholar 

  198. Vila-Bedmar R, Garcia-Guerra L, Nieto-Vazquez I, Mayor F Jr, Lorenzo M, Murga C, Fernandez-Veledo S. GRK2 contribution to the regulation of energy expenditure and brown fat function. FASEB J. 2012;26:3503–14.

    CAS  PubMed  Google Scholar 

  199. Virmani R, Avolio AP, Mergner WJ, Robinowitz M, Herderick EE, Cornhill JF, Guo SY, Liu TH, Ou DY, O’Rourke M. Effect of aging on aortic morphology in populations with high and low prevalence of hypertension and atherosclerosis. Comparison between occidental and Chinese communities. Am J Pathol. 1991;139:1119–29.

    PubMed Central  CAS  PubMed  Google Scholar 

  200. Vu TH, Stamler J, Liu K, McDermott MM, Lloyd-Jones DM, Pirzada A, Garside DB, Daviglus ML. Prospective relationship of low cardiovascular risk factor profile at younger ages to ankle-brachial index: 39-year follow-up-the chicago healthy aging study. J Am Heart Assoc. 2012;1:e001545.

    PubMed Central  PubMed  Google Scholar 

  201. Wang H, Goehring A, Wang KH, Penmatsa A, Ressler R, Gouaux E. Structural basis for action by diverse antidepressants on biogenic amine transporters. Nature. 2013;503:141–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  202. Watari K, Nakaya M, Kurose H. Multiple functions of G protein-coupled receptor kinases. J Mol Signal. 2014;9:1.

    PubMed Central  PubMed  Google Scholar 

  203. Watson LJ, Facundo HT, Ngoh GA, Ameen M, Brainard RE, Lemma KM, Long BW, Prabhu SD, Xuan YT, Jones SP. O-linked beta-N-acetylglucosamine transferase is indispensable in the failing heart. Proc Natl Acad Sci U S A. 2010;107:17797–802.

    PubMed Central  CAS  PubMed  Google Scholar 

  204. Wellenius GA, Wilhelm-Benartzi CS, Wilker EH, Coull BA, Suh HH, Koutrakis P, Lipsitz LA. Ambient particulate matter and the response to orthostatic challenge in the elderly: the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) of Boston study. Hypertension. 2012;59:558–63.

    PubMed Central  CAS  PubMed  Google Scholar 

  205. White M, Roden R, Minobe W, Khan MF, Larrabee P, Wollmering M, Port JD, Anderson F, Campbell D, Feldman AM, et al. Age-related changes in beta-adrenergic neuroeffector systems in the human heart. Circulation. 1994;90:1225–38.

    CAS  PubMed  Google Scholar 

  206. Wills M, Akbar A, Beswick M, Bosch JA, Caruso C, Colonna-Romano G, Dutta A, Franceschi C, Fulop T, Gkrania-Klotsas E, Goronzy J, Griffiths SJ, Henson S, Herndler-Brandstetter D, Hill A, Kern F, Klenerman P, Macallan D, Macualay R, Maier AB, Mason G, Melzer D, Morgan M, Moss P, Nikolich-Zugich J, Pachnio A, Riddell N, Roberts R, Sansoni P, Sauce D, Sinclair J, Solana R, Strindhall J, Trzonkowski P, van Lier R, Vescovini R, Wang G, Westendorp R, Pawelec G. Report from the second cytomegalovirus and immunosenescence workshop. Immunity Ageing. 2011;8(1):10.

    PubMed Central  PubMed  Google Scholar 

  207. Woo AY, Xiao RP. beta-Adrenergic receptor subtype signaling in heart: from bench to bedside. Acta Pharmacol Sin. 2012;33:335–41.

    PubMed Central  CAS  PubMed  Google Scholar 

  208. Wright JJ, Kim J, Buchanan J, Boudina S, Sena S, Bakirtzi K, Ilkun O, Theobald HA, Cooksey RC, Kandror KV, Abel ED. Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding. Cardiovasc Res. 2009;82:351–60.

    PubMed Central  CAS  PubMed  Google Scholar 

  209. Xiao RP. Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins. Science’s STKE. 2001;104:re15.

    Google Scholar 

  210. Xie W, Santulli G, Guo X, Gao M, Chen BX, Marks AR. Imaging atrial arrhythmic intracellular calcium in intact heart. J Mol Cell Cardiol. 2013;64:120–3.

    CAS  PubMed  Google Scholar 

  211. Yuan Q, Chen Z, Santulli G, Gu L, Yang ZG, Yuan ZQ, Zhao YT, Xin HB, Deng KY, Wang SQ, Ji G. Functional Role of Calstabin2 in Age-related Cardiac Alterations. Sci Rep. 2014;4:7425.

    Google Scholar 

  212. Zaccolo M, Pozzan T. Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science. 2002;295:1711–5.

    CAS  PubMed  Google Scholar 

  213. Zamah AM, Delahunty M, Luttrell LM, Lefkowitz RJ. Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system. J Biol Chem. 2002;277:31249–56.

    CAS  PubMed  Google Scholar 

  214. Zeiders JL, Seidler FJ, Iaccarino G, Koch WJ, Slotkin TA. Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling. J Mol Cell Cardiol. 1999;31:413–23.

    CAS  PubMed  Google Scholar 

  215. Zhao L, Yang F, Xu K, Cao H, Zheng GY, Zhang Y, Li J, Cui H, Chen X, Zhu Z, He H, Mo X, Kennedy BK, Suh Y, Zeng Y, Tian XL. Common genetic variants of the beta2-adrenergic receptor affect its translational efficiency and are associated with human longevity. Aging cell. 2012;11:1094–101.

    PubMed Central  CAS  PubMed  Google Scholar 

  216. Ziegler MG, Lake CR, Kopin IJ. Plasma noradrenaline increases with age. Nature. 1976;261:333–5.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gaetano Santulli .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Santulli, G. (2015). The Adrenergic System in Cardiovascular Metabolism and Aging. In: Lymperopoulos, A. (eds) The Cardiovascular Adrenergic System. Springer, Cham. https://doi.org/10.1007/978-3-319-13680-6_6

Download citation

Publish with us

Policies and ethics