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Enhancing Mitochondrial Health to Treat Hypertension

  • Alfonso Eirin
  • Amir Lerman
  • Lilach O. Lerman
Hypertension and Metabolic Syndrome (J Sperati, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hypertension and Metabolic Syndrome

Abstract

Purpose of Review

This review summarizes literature pertaining to the dawning field of therapeutic targeting of mitochondria in hypertension and discusses the potential of these interventions to ameliorate hypertension-induced organ damage.

Recent Findings

In recent years, mitochondrial dysfunction has been reported as an important contributor to the pathogenesis of hypertension-related renal, cardiac, and vascular disease. This in turn prompted development of novel mitochondria-targeted compounds, some of which have shown promising efficacy in experimental studies and safety in clinical trials. In addition, drugs that do not directly target mitochondria have shown remarkable benefits in preserving these organelles in experimental hypertension.

Summary

Enhancing mitochondrial health is emerging as a novel feasible approach to treat hypertension. Future perspectives include mechanistic experimental studies to establish a cause-effect relationship between mitochondrial dysfunction and hypertension and further clinical trials to confirm the reno-, cardio-, and vasculo-protective properties of these compounds in hypertension.

Keywords

Blood pressure Hypertension Mitochondria Heart Kidney Vasculature 

Notes

Funding Information

This study was partly supported by NIH grant numbers DK104273, HL123160, DK100081, DK102325, and DK106427.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67–e492.CrossRefPubMedGoogle Scholar
  2. 2.
    Merai R, Siegel C, Rakotz M, Basch P, Wright J, Wong B, Dhsc, Thorpe P: CDC grand rounds: a public health approach to detect and control hypertension. MMWR Morb Mortal Wkly Rep 2016, 65(45):1261–1264.CrossRefPubMedGoogle Scholar
  3. 3.
    Schmieder RE. End organ damage in hypertension. Dtsch Arztebl Int. 2010;107(49):866–73.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Duchen MR. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Asp Med. 2004;25(4):365–451.CrossRefGoogle Scholar
  5. 5.
    Eirin A, Lerman A, Lerman LO. Mitochondrial injury and dysfunction in hypertension-induced cardiac damage. Eur Heart J. 2014;35(46):3258–66.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Eirin A, Lerman A, Lerman LO. Mitochondria: a pathogenic paradigm in hypertensive renal disease. Hypertension. 2015;65(2):264–70.CrossRefPubMedGoogle Scholar
  7. 7.
    Walther T, Tschope C, Sterner-Kock A, Westermann D, Heringer-Walther S, Riad A, et al. Accelerated mitochondrial adenosine diphosphate/adenosine triphosphate transport improves hypertension-induced heart disease. Circulation. 2007;115(3):333–44.CrossRefPubMedGoogle Scholar
  8. 8.
    Jin K, Vaziri ND. Salt-sensitive hypertension in mitochondrial superoxide dismutase deficiency is associated with intra-renal oxidative stress and inflammation. Clin Exp Nephrol. 2014;18(3):445–52.CrossRefPubMedGoogle Scholar
  9. 9.
    de Cavanagh EM, Toblli JE, Ferder L, Piotrkowski B, Stella I, Inserra F. Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. Am J Physiol Regul Integr Comp Physiol. 2006;290(6):R1616–25.CrossRefPubMedGoogle Scholar
  10. 10.
    Eirin A, Li Z, Zhang X, Krier JD, Woollard JR, Zhu XY, et al. A mitochondrial permeability transition pore inhibitor improves renal outcomes after revascularization in experimental atherosclerotic renal artery stenosis. Hypertension. 2012;60(5):1242–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Eirin A, Ebrahimi B, Kwon SH, Fiala JA, Williams BJ, Woollard JR, et al. Restoration of mitochondrial cardiolipin attenuates cardiac damage in swine renovascular hypertension. J Am Heart Assoc. 2016;5(6)Google Scholar
  12. 12.
    Eirin A, Ebrahimi B, Zhang X, Zhu XY, Woollard JR, He Q, et al. Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease. Cardiovasc Res. 2014;103(4):461–72.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Eirin A, Williams BJ, Ebrahimi B, Zhang X, Crane JA, Lerman A, et al. Mitochondrial targeted peptides attenuate residual myocardial damage after reversal of experimental renovascular hypertension. J Hypertens. 2014;32(1):154–65.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yuan F, Hedayat AF, Ferguson CM, Lerman A, Lerman LO, Eirin A. Mitoprotection attenuates myocardial vascular impairment in porcine metabolic syndrome. Am J Physiol Heart Circ Physiol. 2018;314(3):H669–80.PubMedGoogle Scholar
  15. 15.
    Eirin A, Hedayat AF, Ferguson CM, Textor SC, Lerman A, Lerman LO. Mitoprotection preserves the renal vasculature in porcine metabolic syndrome. Exp Physiol. 2018;103(7):1020–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang S, Li R, Fettermann A, Li Z, Qian Y, Liu Y, et al. Maternally inherited essential hypertension is associated with the novel 4263A>G mutation in the mitochondrial tRNAIle gene in a large Han Chinese family. Circ Res. 2011;108(7):862–70.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wilson FH, Hariri A, Farhi A, Zhao H, Petersen KF, Toka HR, et al. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science. 2004;306(5699):1190–4.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Osellame LD, Blacker TS, Duchen MR. Cellular and molecular mechanisms of mitochondrial function. Best Pract Res Clin Endocrinol Metab. 2012;26(6):711–23.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171(8):2029–50.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sparagna GC, Johnson CA, McCune SA, Moore RL, Murphy RC. Quantitation of cardiolipin molecular species in spontaneously hypertensive heart failure rats using electrospray ionization mass spectrometry. J Lipid Res. 2005;46(6):1196–204.CrossRefPubMedGoogle Scholar
  21. 21.
    Zachman DK, Chicco AJ, McCune SA, Murphy RC, Moore RL, Sparagna GC. The role of calcium-independent phospholipase A2 in cardiolipin remodeling in the spontaneously hypertensive heart failure rat heart. J Lipid Res. 2010;51(3):525–34.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Schug ZT, Gottlieb E. Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim Biophys Acta. 2009;1788(10):2022–31.CrossRefPubMedGoogle Scholar
  23. 23.
    Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014;171(8):2017–28.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintron M, Chen T, et al. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res. 2011;108(7):837–46.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, et al. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013;6(5):1067–76.CrossRefPubMedGoogle Scholar
  26. 26.
    Eirin A, Woollard JR, Ferguson CM, Jordan KL, Tang H, Textor SC, et al. The metabolic syndrome induces early changes in the swine renal medullary mitochondria. Transl Res. 2017;184:45–56 e49.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yuan F, Woollard JR, Jordan KL, Lerman A, Lerman LO, Eirin A. Mitochondrial targeted peptides preserve mitochondrial organization and decrease reversible myocardial changes in early swine metabolic syndrome. Cardiovasc Res. 2018;114(3):431–42.CrossRefPubMedGoogle Scholar
  28. 28.
    •• Saad A, Herrmann SMS, Eirin A, Ferguson CM, Glockner JF, Bjarnason H, et al. Phase 2a clinical trial of mitochondrial protection (elamipretide) during stent revascularization in patients with atherosclerotic renal artery stenosis. Circ Cardiovasc Interv. 2017;10(9) This pilot study showed that adjunctive mitoprotection during renal revascularization attenuates post-procedural hypoxia and improved kidney function in human renovascular hypertension. PubMedGoogle Scholar
  29. 29.
    Szeto HH. Pharmacologic approaches to improve mitochondrial function in AKI and CKD. J Am Soc Nephrol. 2017;28(10):2856–65.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lebrasseur NK, Duhaney TA, De Silva DS, Cui L, Ip PC, Joseph L, et al. Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension. Hypertension. 2007;50(3):489–96.CrossRefPubMedGoogle Scholar
  31. 31.
    Sporkova A, Certikova Chabova V, Dolezelova S, Jichova S, Kopkan L, Vanourkova Z, et al. Fenofibrate attenuates hypertension in Goldblatt hypertensive rats: role of 20-hydroxyeicosatetraenoic acid in the nonclipped kidney. Am J Med Sci. 2017;353(6):568–79.CrossRefPubMedGoogle Scholar
  32. 32.
    Hou X, Shen YH, Li C, Wang F, Zhang C, Bu P, et al. PPARα agonist fenofibrate protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress and MAPK activity. Biochem Biophys Res Commun. 2010;394(3):653–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Gilbert K, Nian H, Yu C, Luther JM, Brown NJ. Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension. J Hypertens. 2013;31(4):820–9.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Duhaney TA, Cui L, Rude MK, Lebrasseur NK, Ngoy S, De Silva DS, et al. Peroxisome proliferator-activated receptor alpha-independent actions of fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload. Hypertension. 2007;49(5):1084–94.CrossRefPubMedGoogle Scholar
  35. 35.
    Suzuki T, Yamaguchi H, Kikusato M, Hashizume O, Nagatoishi S, Matsuo A, et al. Mitochonic acid 5 binds mitochondria and ameliorates renal tubular and cardiac myocyte damage. J Am Soc Nephrol. 2016;27(7):1925–32.CrossRefPubMedGoogle Scholar
  36. 36.
    Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.CrossRefPubMedGoogle Scholar
  37. 37.
    •• Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cocheme HM, et al. Dominiczak AF: Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension. 2009;54(2):322–8. This article reported that treatment with mitochondria-targeted antioxidants protected against the development of hypertension and reduced cardiac hypertrophy in hypertensive rats. CrossRefPubMedGoogle Scholar
  38. 38.
    Ribeiro Junior RF, Dabkowski ER, Shekar KC, O Connell KA, Hecker PA, Murphy MP. MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload. Free Radic Biol Med. 2018;117:18–29.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Peixoto EB, Pessoa BS, Biswas SK, Lopes de Faria JB. Antioxidant SOD mimetic prevents NADPH oxidase-induced oxidative stress and renal damage in the early stage of experimental diabetes and hypertension. Am J Nephrol. 2009;29(4):309–18.CrossRefPubMedGoogle Scholar
  40. 40.
    Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, McCann L, Lewis W, et al. Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res. 2010;107(1):106–16.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Lowes DA, Webster NR, Murphy MP, Galley HF. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br J Anaesth. 2013;110(3):472–80.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Seifi B, Kadkhodaee M, Karimian SM, Zahmatkesh M, Shams S, Bakhshi E. Reduction of kidney damage by supplementation of vitamins C and E in rats with deoxycorticosterone-salt-induced hypertension. Iran J Kidney Dis. 2009;3(4):197–202.PubMedGoogle Scholar
  43. 43.
    Versari D, Daghini E, Rodriguez-Porcel M, Sattler K, Galili O, Pilarczyk K, et al. Chronic antioxidant supplementation impairs coronary endothelial function and myocardial perfusion in normal pigs. Hypertension. 2006;47(3):475–81.CrossRefPubMedGoogle Scholar
  44. 44.
    Daghini E, Zhu XY, Versari D, Bentley MD, Napoli C, Lerman A, et al. Antioxidant vitamins induce angiogenesis in the normal pig kidney. Am J Physiol Renal Physiol. 2007;293(1):F371–81.CrossRefPubMedGoogle Scholar
  45. 45.
    Garcia-Redondo AB, Briones AM, Beltran AE, Alonso MJ, Simonsen U, Salaices M. Hypertension increases contractile responses to hydrogen peroxide in resistance arteries through increased thromboxane A2, Ca2+, and superoxide anion levels. J Pharmacol Exp Ther. 2009;328(1):19–27.CrossRefPubMedGoogle Scholar
  46. 46.
    Guimaraes DD, Carvalho CC, Braga VA. Scavenging of NADPH oxidase-derived superoxide anions improves depressed baroreflex sensitivity in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 2012;39(4):373–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Palikaras K, Tavernarakis N. Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp Gerontol. 2014;56:182–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Hock MB, Kralli A. Transcriptional control of mitochondrial biogenesis and function. Annu Rev Physiol. 2009;71:177–203.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Wills LP, Trager RE, Beeson GC, Lindsey CC, Peterson YK, Beeson CC, et al. The beta2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis. J Pharmacol Exp Ther. 2012;342(1):106–18.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Fedorova LV, Sodhi K, Gatto-Weis C, Puri N, Hinds TD Jr, Shapiro JI, et al. Peroxisome proliferator-activated receptor delta agonist, HPP593, prevents renal necrosis under chronic ischemia. PLoS One. 2013;8(5):e64436.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Szabo A, Sumegi K, Fekete K, Hocsak E, Debreceni B, Setalo G Jr, et al. Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases. Biochem Pharmacol. 2018;150:86–96.CrossRefPubMedGoogle Scholar
  52. 52.
    Liu X, Tan H, Liu X, Wu Q. Correlation between the expression of Drp1 in vascular endothelial cells and inflammatory factors in hypertension rats. Exp Ther Med. 2018;15(4):3892–8.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Sumida M, Doi K, Ogasawara E, Yamashita T, Hamasaki Y, Kariya T, et al. Regulation of mitochondrial dynamics by dynamin-related protein-1 in acute cardiorenal syndrome. J Am Soc Nephrol. 2015;26(10):2378–87.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation. 2010;121(18):2012–22.CrossRefPubMedGoogle Scholar
  55. 55.
    Ikeda Y, Shirakabe A, Maejima Y, Zhai P, Sciarretta S, Toli J, et al. Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res. 2015;116(2):264–78.CrossRefPubMedGoogle Scholar
  56. 56.
    Shen Z, Li Y, Gasparski AN, Abeliovich H, Greenberg ML. Cardiolipin regulates mitophagy through the protein kinase C pathway. J Biol Chem. 2017;292(7):2916–23.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Singh D, Chander V, Chopra K. Cyclosporine protects against ischemia/reperfusion injury in rat kidneys. Toxicology. 2005;207(3):339–47.CrossRefPubMedGoogle Scholar
  58. 58.
    Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, et al. Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med. 2015;373(11):1021–31.CrossRefPubMedGoogle Scholar
  59. 59.
    Bloom IT, Bentley FR, Garrison RN. Acute cyclosporine-induced renal vasoconstriction is mediated by endothelin-1. Surgery. 1993;114(2):480–7. discussion 487-488PubMedGoogle Scholar
  60. 60.
    Calo L, Semplicini A, Davis PA, Bonvicini P, Cantaro S, Rigotti P, et al. Cyclosporin-induced endothelial dysfunction and hypertension: are nitric oxide system abnormality and oxidative stress involved? Transpl Int. 2000;13(Suppl 1):S413–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Juhaszova M, Zorov DB, Yaniv Y, Nuss HB, Wang S, Sollott SJ. Role of glycogen synthase kinase-3beta in cardioprotection. Circ Res. 2009;104(11):1240–52.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, et al. Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection. Hypertension. 2011;57(1):110–5.CrossRefPubMedGoogle Scholar
  63. 63.
    Barillas R, Friehs I, Cao-Danh H, Martinez JF, del Nido PJ. Inhibition of glycogen synthase kinase-3beta improves tolerance to ischemia in hypertrophied hearts. Ann Thorac Surg. 2007;84(1):126–33.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Gonzalez Arbelaez LF, Perez Nunez IA, Mosca SM. Gsk-3beta inhibitors mimic the cardioprotection mediated by ischemic pre- and postconditioning in hypertensive rats. Biomed Res Int. 2013;2013:317456.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Neuzil J, Widen C, Gellert N, Swettenham E, Zobalova R, Dong LF, et al. Mitochondria transmit apoptosis signalling in cardiomyocyte-like cells and isolated hearts exposed to experimental ischemia-reperfusion injury. Redox Rep. 2007;12(3):148–62.CrossRefPubMedGoogle Scholar
  66. 66.
    Zhang X, Li ZL, Crane JA, Jordan KL, Pawar AS, Textor SC, et al. Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension. Hypertension. 2014;64(1):87–93.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Abadir PM, Foster DB, Crow M, Cooke CA, Rucker JJ, Jain A, et al. Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci U S A. 2011;108(36):14849–54.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Costa LE, La-Padula P, Lores-Arnaiz S, D'Amico G, Boveris A, Kurnjek ML, et al. Long-term angiotensin II inhibition increases mitochondrial nitric oxide synthase and not antioxidant enzyme activities in rat heart. J Hypertens. 2002;20(12):2487–94.CrossRefPubMedGoogle Scholar
  69. 69.
    de Cavanagh EM, Inserra F, Ferder L, Fraga CG. Enalapril and captopril enhance glutathione-dependent antioxidant defenses in mouse tissues. Am J Physiol Regul Integr Comp Physiol. 2000;278(3):R572–7.CrossRefPubMedGoogle Scholar
  70. 70.
    Piotrkowski B, Fraga CG, de Cavanagh EM. Mitochondrial function and nitric oxide metabolism are modified by enalapril treatment in rat kidney. Am J Physiol Regul Integr Comp Physiol. 2007;292(4):R1494–501.CrossRefPubMedGoogle Scholar
  71. 71.
    •• McLachlan J, Beattie E, Murphy MP, Koh-Tan CH, Olson E, Beattie W, et al. Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function. J Hypertens. 2014;32(3):555–64. This article revealed that combining antihypertensives and mitochondria-targeted peptides has additional therapeutic benefit for attenuating hypertension-induced myocardial damage. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Alfonso Eirin
    • 1
  • Amir Lerman
    • 2
  • Lilach O. Lerman
    • 1
    • 2
  1. 1.Division of Nephrology and HypertensionMayo ClinicRochesterUSA
  2. 2.Department of Cardiovascular DiseasesMayo ClinicRochesterUSA

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