Amino Acids

, Volume 50, Issue 6, pp 747–754 | Cite as

Arginase inhibition prevents the development of hypertension and improves insulin resistance in obese rats

  • Kelly J. Peyton
  • Xiao-ming Liu
  • Ahmad R. Shebib
  • Fruzsina K. Johnson
  • Robert A. Johnson
  • William Durante
Original Article
  • 109 Downloads

Abstract

This study investigated the temporal activation of arginase in obese Zucker rats (ZR) and determined if arginase inhibition prevents the development of hypertension and improves insulin resistance in these animals. Arginase activity, plasma arginine and nitric oxide (NO) concentration, blood pressure, and insulin resistance were measured in lean and obese animals. There was a chronological increase in vascular and plasma arginase activity in obese ZR beginning at 8 weeks of age. The increase in arginase activity in obese animals was associated with a decrease in insulin sensitivity and circulating levels of arginine and NO. The rise in arginase activity also preceded the increase in blood pressure in obese ZR detected at 12 weeks of age. Chronic treatment of 8-week-old obese animals with an arginase inhibitor or l-arginine for 4 weeks prevented the development of hypertension and improved plasma concentrations of arginine and NO. Arginase inhibition also improved insulin sensitivity in obese ZR while l-arginine supplementation had no effect. In conclusion, arginase inhibition prevents the development of hypertension and improves insulin sensitivity while l-arginine administration only mitigates hypertension in obese animals. Arginase represents a promising therapeutic target in ameliorating obesity-associated vascular and metabolic dysfunction.

Keywords

Arginine Arginase Obesity Hypertension 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. The article does not contain any studies with human participants performed by any of the authors, thus no informed consent was required in the study.

References

  1. Abdelkawy KS, Lack K, Elbarbry F (2017) Pharmacokinetics and pharmacodynamics of promising arginase inhibitors. Eur J Drug Metab Pharmacokinet 42:355–370CrossRefPubMedGoogle Scholar
  2. Ali MA, Strandvik B, Palme-Kilander C, Yngve A (2013) Lower polyamine levels in breast milk of obese mothers compared to mothers with normal body weight. J Hum Nutr Diet 26(Suppl 1):164–170CrossRefPubMedGoogle Scholar
  3. Assumpcao CR, Brunini TM, Pereira NR, Godoy-Matsos AF, Siqueira MA, Mann GE et al (2016) Insulin resistance in obesity and metabolic syndrome: is there a connection with platelet l-arginine transport? Blood Cells Mol Dis 45:338–342CrossRefGoogle Scholar
  4. Bagnost T, Berthelot A, Bouhaddi M, Laurent P, Andre C, Guillame T et al (2008) Treatment with the arginase inhibitor Nω-hydroxy-nor-l-arginine improves vascular function and lowers blood pressure in adult spontaneously hypertensive rat. J Hypertens 26:1110–1118CrossRefPubMedGoogle Scholar
  5. Bhatta A, Yao L, Xu Z, Toque HA, Chen J, Atawia RT et al (2017) Obesity-induced vascular dysfunction and arterial stiffening required endothelial cell arginase 1. Cardiovasc Res 113:1664–1676CrossRefPubMedGoogle Scholar
  6. Bohm C, Benz V, Clemenz M, Sprang C, Hoft B, Kintscher U et al (2013) Sexual dimorphism in obesity-mediated left ventricular hypertrophy. Am J Physiol Heart Circ Physiol 305:H211–H218CrossRefPubMedGoogle Scholar
  7. Codoner-Franch P, Tavarez-Alonso S, Murria-Estal R, Herrera-Martin G, Alonso-Iglesias E (2011) Polyamines are increased in obese children and are related to markers of oxidative and nitrosative stress and angiogenesis. J Clin Endocrinol Metab 96:2821–2825CrossRefPubMedGoogle Scholar
  8. De Castro Barbosa T, Lourenco Poyares L, Fabres Muchado U, Nunes MT (2006) Chronic oral administration of arginine induces GH gene expression and insulin resistance. Life Sci 79:1444–1449CrossRefGoogle Scholar
  9. Durante W (2013) Role of arginase in vessel wall remodeling. Front Immunol 4:111CrossRefPubMedPubMedCentralGoogle Scholar
  10. Durante W, Schini VB, Catovsky S, Kroll MH, Vanhoutte PM, Schafer AI (1993) Plasmin potentiates induction of nitric oxide synthesis by interleukin-1β in vascular smooth muscle cells. Am J Physiol 264:H617–H624CrossRefPubMedGoogle Scholar
  11. Durante W, Liao L, Iftikhar I, O’Brien WE, Schafer AI (1996) Differential regulation of l-arginine transport and nitric oxide production by vascular smooth muscle and endothelium. Circ Res 78:1075–1082CrossRefPubMedGoogle Scholar
  12. Durante W, Johnson FK, Johnson RA (2007) Arginase: a critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol 34:906–911CrossRefPubMedPubMedCentralGoogle Scholar
  13. El Assar M, Angulo J, Santos-Ruiz M, Ruiz de Adana JC, Pindado ML, Sanchez-Ferrer A et al (2016) Asymmetric dimethylarginine (ADMA) elevation and arginase upregulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans. J Physiol 594:3045–3060CrossRefPubMedPubMedCentralGoogle Scholar
  14. El Bassossy HM, El-Fawal R, Fahmy A (2012) Arginase inhibition alleviates hypertension associated with diabetes: effect on endothelial dependent relaxation and NO production. Vascul Pharmacol 57:194–200CrossRefPubMedGoogle Scholar
  15. El-Bassossy HM, El-Fawal R, Fahmy A, Watson ML (2013) Arginase inhibition alleviates hypertension in the metabolic syndrome. Br J Pharmacol 169:693–703CrossRefPubMedPubMedCentralGoogle Scholar
  16. Erdely A, Kepka-Lenhart D, Salmen-Muniz R, Chapman R, Hulderman T, Kashen M, Simeonova PP, Morris JM Jr (2010) Arginase activities and global arginine bioavailability in wild-type and ApoE-deficient mice: responses to high fat and high cholesterol diets. PLoS One 5:e15253CrossRefPubMedPubMedCentralGoogle Scholar
  17. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL (2016) Trends in obesity among adults in the United States, 2005–2014. JAMA 315:2284–2291CrossRefPubMedGoogle Scholar
  18. Fu WJ, Haynes TE, Kohli R, Hu J, Shi W, Spencer TE et al (2005) Dietary l-arginine supplementation reduces fat mass in Zucker diabetic fatty rats. J Nutr 135:714–721CrossRefPubMedGoogle Scholar
  19. Gao X, Xu X, Belmadani S, Park Y, Tang Z, Am Feldman et al (2007) TNF-alpha contributes to endothelial dysfunction by upregulating arginase in ischemia-reperfusion injury. Arterioscler Thromb Vasc Biol 27:1269–1275CrossRefPubMedGoogle Scholar
  20. Garrison RJ, Kannel WB, Stokes J 3rd, Castelli WP (1987) Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev Med 16:235–251CrossRefPubMedGoogle Scholar
  21. Giri H, Muthuramu I, Dhar M, Rathnakumar K, Ram U, Dixit M (2012) Protein tyrosine phosphatase SHP2 mediates chronic insulin-induced endothelial inflammation. Arterioscler Thromb Vasc Biol 32:1943–1950CrossRefPubMedGoogle Scholar
  22. Gruber HJ, Mayer C, Mangge H, Fauler G, Grandits N, Wilders-Truschnig M (2008) Obesity reduces the bioavailability of nitric oxide in juveniles. Int J Obes (Lond) 32:826–831CrossRefGoogle Scholar
  23. Holowatz LA, Kenney WL (2007) Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilation in hypertensive humans. J Physiol 581:863–872CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hu H, Moon J, Chung JH, Kim OY, Yu R, Shin MJ (2015) Arginase inhibition ameliorates adipose tissue inflammation in mice with diet-induced obesity. Biochem Biophys Res Commun 464:840–847CrossRefPubMedGoogle Scholar
  25. Huynh HH, Harris EE, Chin-Dusting JFP, Andrews LK (2009) The vascular effects of different arginase inhibitors in rat isolated aorta and mesenteric arteries. Br J Pharmacol 156:84–93CrossRefPubMedPubMedCentralGoogle Scholar
  26. Jamdar SC, Cao WF, Samaniego E (1996) Relationship between adipose polyamine concentrations and triacylglycerol synthetic enzymes in lean and obese Zucker rats. Enzyme Protein 49:222–230CrossRefPubMedGoogle Scholar
  27. Jobgen W, Meininger CJ, Jobgen SC, Li P, Lee MJ, Smith SB et al (2009) Dietary l-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats. J Nutr 139:230–237CrossRefPubMedPubMedCentralGoogle Scholar
  28. Johnson FK, Peyton KJ, Liu XM, Azam MA, Shebib AR, Johnson RA et al (2015) Arginase promotes endothelial dysfunction and hypertension in obese rats. Obesity 23:445–452CrossRefGoogle Scholar
  29. Jung C, Figulla HR, Lichtenauer M, Franz M, Pernow J (2014) Increased levels of circulating arginase I in overweight compared to normal weight adolescents. Pediatr Diabetes 15:51–56CrossRefPubMedGoogle Scholar
  30. Kawano T, Nomura M, Nisikado A, Nakaya Y, Ito S (2003) Supplementation of l-arginine improves hypertension and lipid metabolism but not insulin resistance in diabetic rats. Life Sci 73:3017–3026CrossRefPubMedGoogle Scholar
  31. Kim OY, Lee SM, Chung JH, Do HJ, Moon J, Shin MJ (2012) Arginase I and the very low-density lipoprotein receptor are associated with phenotypic biomarkers for obesity. Nutrition 28:635–639CrossRefPubMedGoogle Scholar
  32. Kovamees O, Shemyakin A, Eriksson M, Angelin B, Pernow J (2016) Arginase inhibition improves endothelial function with familial hypercholesterolemia irrespective of their cholesterol level. J Intern Med 279:477–484CrossRefPubMedGoogle Scholar
  33. Landsberg L, Aronne LJ, Beilin LJ, Burke V, Igel LI, Lloyd-Jones D et al (2013) Obesity-related hypertension: pathogenesis, cardiovascular risk, and treatment—a position paper of the Obesity Society and the American Society of Hypertension. Obesity 21:8–24CrossRefPubMedGoogle Scholar
  34. Malnick SD, Knobler H (2006) The medical complications of obesity. QJM 99:565–579CrossRefPubMedGoogle Scholar
  35. Manrique C, Lastra G, Habibi J, Pulakat L, Schneider R, Durante W et al (2011) Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat. Metabolism 60:1757–1766CrossRefPubMedPubMedCentralGoogle Scholar
  36. Manrique C, DeMarco VG, Aroor AR, Mugerfeld I, Garro M, Habibi J et al (2013) Obesity and insulin resistance induce early development of diastolic dysfunction in young female mice fed a western diet. Endocrinology 154:3632–3642CrossRefPubMedPubMedCentralGoogle Scholar
  37. McNeal CJ, Meininger CJ, Reddy D, Wilborn CD, Wu G (2016) Safety and efficacy of arginine in adults. J Nutr 146(Suppl):2587S–2593SCrossRefPubMedGoogle Scholar
  38. Ming X-F, Rajapakse AG, Yepuri G, Xiong Y, Carvas JM, Ruffieux J et al (2012) Arginase II promotes macrophage inflammatory responses through mitochondrial reactive oxygen species, contributing to insulin resistance and atherogenesis. J Am Heart Assoc 1:e000992CrossRefPubMedPubMedCentralGoogle Scholar
  39. Mirmiran P, Bahadoran Z, Ghasemi A, Azizi F (2016) The association of dietary l-arginine intake and serum nitric oxide metabolites in adults: a population-based study. Nutrients 8:311CrossRefPubMedCentralGoogle Scholar
  40. Monti LD, Setola E, Lucotti PC, Marracco-Trischitta MM, Comola M, Galluccio E et al (2012) Effect of long-term oral l-arginine supplementation on glucose metabolism: a randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 14:893–900CrossRefPubMedGoogle Scholar
  41. Moon J, Do HJ, Cho Y, Shin MJ (2014) Arginase inhibition ameliorates hepatic metabolic abnormalities in obese mice. PLoS One 9:7Google Scholar
  42. Morris SM Jr (2007) Arginine metabolism: boundaries of our knowledge. J Nutr 137(Suppl. 2):1602S–1609SCrossRefPubMedGoogle Scholar
  43. Nedungadi TP, Clegg DJ (2009) Sexual dimorphism in body fat distribution and risk for cardiovascular diseases. J Cardiovasc Transl Res 2:321–327CrossRefPubMedGoogle Scholar
  44. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF et al (2009) A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9:311–326CrossRefPubMedPubMedCentralGoogle Scholar
  45. Pernow J, Jung C (2013) Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal? Cardiovasc Res 98:334–343CrossRefPubMedGoogle Scholar
  46. Pudlo M, Demougeot C, Girard-Thernier C (2017) Arginase inhibitors: a rational approach over one century. Med Res Rev 37:475–513CrossRefPubMedGoogle Scholar
  47. Quitter F, Figulla HR, Ferrari M, Pernow J, Jung C (2013) Increased arginase levels in heart failure represent a therapeutic target to rescue microvascular perfusion. Clin Hemorrheol Microcirc 54:75–85Google Scholar
  48. Rajapakse NW, Karim F, Straznicky NE, Fernandez S, Evans RG, Head GA et al (2014) Augmented endothelial-specific l-arginine transport prevents obesity-induced hypertension. Acta Physiol (Oxf) 212:39–48CrossRefGoogle Scholar
  49. Rajapakse NW, Head GA, Kaye DM (2016) Say NO to obesity-related hypertension: role of the l-arginine-nitric oxide pathway. Hypertension 67:813–819CrossRefPubMedGoogle Scholar
  50. Reid KM, Tsung A, Kaizu T, Jeyabalan G, Ikeda A, Shao L et al (2007) Liver I/R injury is improved by the arginase inhibitor, N(omega)-hydroxy-nor-l-arginine (nor-NOHA). Am J Physiol Gastrointest Liver Physiol 292:G512–G527CrossRefPubMedGoogle Scholar
  51. Riazi S, Madal-Halagappa VK, Dantas AP, Hu X, Ecelbarger CA (2007) Sex differences in renal nitric oxide synthase, NAD(P)H oxidase, and blood pressure in obese Zucker rats. Gend Med 4:214–229CrossRefPubMedGoogle Scholar
  52. Ryoo S, Lemmon CA, Soucy KG, Gupta G, White AR, Nyhan D et al (2006) Oxidized low-density lipoprotein-dependent endothelial arginase II activation contributes to impaired nitric oxide signaling. Circ Res 99:951–960CrossRefPubMedGoogle Scholar
  53. Ryoo S, Gupta G, Benjo A, Lim HK, Camara A, Sikka G et al (2008) Endothelial arginase II. A novel target for the treatment of atherosclerosis. Circ Res 102:923–932CrossRefPubMedGoogle Scholar
  54. Sailer M, Dahlhoff C, Giesbertz P, Eidens MK, de Wit N, Rubio-Aliaga I et al (2013) Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome. PLoS One 8:e63950CrossRefPubMedPubMedCentralGoogle Scholar
  55. Shatanawi A, Romero M, Iddings JA, Chandra S, Umapathy NS, Verin AD et al (2011) Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway. Am J Physiol Cell Physiol 300:C1181–C1192CrossRefPubMedPubMedCentralGoogle Scholar
  56. She P, Van Horne C, Reid T, Hutson SM, Cooney RN, Lynch CJ (2007) Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab 293:E1552–E1563CrossRefPubMedPubMedCentralGoogle Scholar
  57. Shemyakin A, Kovamees O, Rafnsson A, Bohm F, Svenarud P, Settergren M et al (2012) Arginase inhibition improves endothelial function in patients with coronary artery disease and type 2 diabetes mellitus. Circulation 126:2943–2950CrossRefPubMedGoogle Scholar
  58. Siervo M, Bluck LJ (2012) In vivo nitric oxide synthesis, insulin sensitivity, and asymmetric dimethylarginine in obese subjects without or with metabolic syndrome. Metabolism 61:680–688CrossRefPubMedGoogle Scholar
  59. Sjoholm A, Arkhammar P, Berggren PO, Andersson A (2001) Polyamines in pancreatic islets of obese-hyperglycemic (ob/ob) mice of different ages. Am J Physiol Cell Physiol 280:C317–C323CrossRefPubMedGoogle Scholar
  60. Steppan J, Tran HT, Bead VR, Oh YJ, Sikka G, Bivalacqua TJ et al (2016) Arginase inhibition reverses endothelial dysfunction, pulmonary hypertension, and vascular stiffness in transgenic sickle cell mice. Anesth Analg 123:652–658CrossRefPubMedPubMedCentralGoogle Scholar
  61. Sun CK, Zhang XY, Zimmermann A, Davis G, Wheatley AM (2001) Effect of ischemia-reperfusion injury on the microcirculation of the steatotic liver of the Zucker rat. Transplantation 72:1625–1631CrossRefPubMedGoogle Scholar
  62. Weisbrod RM, Shiang T, Al Sayah L, Fry JL, Bajpai S, Reinhart-Kin CA et al (2013) Arterial stiffening precedes systolic hypertension in diet-induced obesity. Hypertension 62:1105–1110CrossRefPubMedPubMedCentralGoogle Scholar
  63. Zucker LM (1965) Hereditary obesity in the rat associated with hyperlipidemia. Ann N Y Acad Sci 131:447–458CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medical Pharmacology and Physiology, School of MedicineUniversity of MissouriColumbiaUSA
  2. 2.College of Osteopathic MedicineWilliam Cary UniversityHattiesburgUSA

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