Skip to main content
SpringerLink
Log in

Contribution of hydrogen sulfide and nitric oxide to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

It is well known that exercise training attenuates aortic remodeling and improves endothelial function in spontaneously hypertensive rats (SHR). However, the underlying molecular mechanism remains unclear. Hydrogen sulfide (H2S) and nitric oxide (NO), as two established physiologic messenger molecules, have important roles in the development of aortic remodeling and endothelial dysfunction in hypertensive animals and patients. In this work, it was found that exercise training had no significant effect on blood pressure, but effectively attenuated baroreflex dysfunction in SHR. Exercise training in SHR attenuated aortic remodeling and improved endothelium-mediated vascular relaxations of aortas in response to acetylcholine. Interestingly, exercise training in SHR restored plasma H2S levels and aortic H2S formation and enhanced levels of mRNA for cystathionine γ-lyase in aortas. Furthermore, exercise training in SHR resulted in augmentation of nitrite and nitrate (NOx) contents and reduction of asymmetric dimethylarginine contents of aortas, upregulation of dimethylarginine dimethylaminohydrolase 2, and phosphorylation of nitric oxide synthase 3, but had no significant effect on protein levels of NOS3. In addition, exercise training could effectively reduce malondialdehyde production and suppressed formation of O2 −, and OONO− in aortas of SHR through enhancing activities of superoxide dismutase and catalase, and suppressing NADPH oxidase activity. In conclusion, exercise training ameliorates aortic hypertrophy and endothelial dysfunction, possibly via restoring bioavailabilities of hydrogen sulfide and nitric oxide in SHR.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Panza JA, García CE, Kilcoyne CM, Quyyumi AA, Cannon RO (1995) Impaired endothelium-dependent vasodilation in patients with essential hypertension:evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation 91:1732–1738

    Article  PubMed  CAS  Google Scholar 

  2. Konishi M, Su C (1983) Role of endothelium in dilator responses of spontaneously hypertensive rat arteries. Hypertension 5:881–886

    Article  PubMed  CAS  Google Scholar 

  3. Javkhedkar AA, Lokhandwala MF, Banday AA (2012) Defective nitric oxide production impairs angiotensin II-induced Na/K-ATPase regulation in spontaneously hypertensive rats. Am J Physiol Renal Physiol 302:F47–F51

    Article  PubMed  CAS  Google Scholar 

  4. Al-Magableh MR, Hart JL (2011) Mechanism of vasorelaxation and role of endogenous hydrogen sulfide production in mouse aorta. Naunyn Schmiedebergs Arch Pharmacol 383:403–413

    Article  PubMed  CAS  Google Scholar 

  5. Ulker S, McKeown PP, Bayraktutan U (2003) Vitamins reverse endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities. Hypertension 41:534–539

    Article  PubMed  Google Scholar 

  6. Vaziri ND, Ni Z, Oveisi F (1998) Upregulation of renal and vascular nitric oxide synthase in young spontaneously hypertensive rats. Hypertension 31:1248–1254

    Article  PubMed  CAS  Google Scholar 

  7. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377:239–242

    Article  PubMed  CAS  Google Scholar 

  8. França-Silva MS, Monteiro MM, Queiroz TM, Santos AF, Athayde-Filho PF, Braga VA (2012) The new nitric oxide donor 2-nitrate-1,3-dibuthoxypropan alters autonomic function in spontaneously hypertensive rats. Auton Neurosci 171:28–35

    Article  PubMed  Google Scholar 

  9. Shi YX, Chen Y, Zhu YZ, Huang GY, Moore PK, Huang SH, Yao T, Zhu YC (2007) Chronic sodium hydrosulfide treatment decreases medial thickening of intramyocardial coronary arterioles, interstitial fibrosis, and ROS production in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 293:H2093–H2100

    Article  PubMed  CAS  Google Scholar 

  10. Lu M, Liu YH, Goh HS, Wang JJ, Yong QC, Wang R, Bian JS (2010) Hydrogen sulfide inhibits plasma renin activity. J Am Soc Nephrol 21:993–1002

    Article  PubMed  CAS  Google Scholar 

  11. Delp MD, Laughlin MH (1997) Time course of enhanced endothelium mediated dilation in aorta of trained rats. Med Sci Sports Exerc 29:1454–1461

    Article  PubMed  CAS  Google Scholar 

  12. Yen MH, Yang JH, Sheu JR, Lee YM, Ding YA (1995) Chronic exercise enhances endothelium-mediated dilation in spontaneously hypertensive rats. Life Sci 57:2205–2213

    Article  PubMed  CAS  Google Scholar 

  13. Moraes-Teixeira JA, Felix A, Fernandes-Santos C, Moura AS, Mandarim-de-Lacerda CA, Carvalho JJ (2010) Exercise training enhances elastin, fibrillin and nitric oxide in the aorta wall of spontaneously hypertensive rats. Exp Mol Pathol 89:351–357

    Article  CAS  Google Scholar 

  14. Husain K (2004) Physical conditioning modulates rat cardiac VEGF gene expression in nitric oxide-deficient hypertension. Biochem Biophys Res Commun 320:1169–1174

    Article  PubMed  CAS  Google Scholar 

  15. Zheng H, Yu YS (2012) Chronic hydrogen-rich saline treatment attenuates vascular dysfunction in spontaneous hypertensive rats. Biochem Pharmacol 83:1269–1277

    Article  PubMed  CAS  Google Scholar 

  16. Peng H, Carretero OA, Vuljaj N, Liao TD, Motivala A, Peterson EL, Rhaleb NE (2005) Angiotensin-converting enzyme inhibitors. A new mechanism of action. Circulation 112:2436–2445

    Article  PubMed  CAS  Google Scholar 

  17. Verhoeff FH (1908) Some new staining methods of wide applicability including a rapid differential stain for elastic tissue. JAMA 50:876–877

    Article  Google Scholar 

  18. Scalera F, Borlak J, Beckmann B, Martens-Lobenhoffer J, Thum T, Tager M, Bode-Boger SM (2004) Endogenous nitric oxide synthesis inhibitor asymmetric dimethyl l-arginine accelerates endothelial cell senescence. Arterioscler Thromb Vasc Biol 24:1816–1822

    Article  PubMed  CAS  Google Scholar 

  19. Elks CM, Mariappan N, Haque M, Guggilam A, Majid DS, Francis J (2009) Chronic NF-kB blockade reduces cytosolic and mitochondrial oxidative stress and attenuates renal injury and hypertension in SHR. Am J Physiol Renal Physiol 296:F298–F305

    Article  PubMed  CAS  Google Scholar 

  20. Li YL, Gao L, Zucker IH, Schultz HD (2007) NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits. Cardiovasc Res 75:546–554

    Article  PubMed  CAS  Google Scholar 

  21. Mariappan N, Soorappan RN, Haque M, Sriramula S, Francis J (2007) TNF-α-induced mitochondrial oxidative stress and cardiac dysfunction, restoration by superoxide dismutase mimetic Tempol. Am J Physiol Heart Circ Physiol 293:H2726–H2737

    Article  PubMed  CAS  Google Scholar 

  22. Su DF, Miao CY (2005) Reduction of blood pressure variability: a new strategy for the treatment of hypertension. Trends Pharmacol Sci 26:388–390

    Article  PubMed  CAS  Google Scholar 

  23. La Rovere MT, Specchia G, Mortara A, Specchia G (1988) Baroreflex sensitivity, clinical correlates and cardiovascular morality among patients with a first myocardial infarction: a prospective study. Circulation 78:816–824

    Article  PubMed  CAS  Google Scholar 

  24. Mortara A, La Rovere MT, Pinna GD, Prpa A, Maestri R, Febo O, Pozzoli M, Opasich C, Tavazzi L (1997) Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation 96:3450–3458

    Article  PubMed  CAS  Google Scholar 

  25. Yu YS, Xie HH, Li L, Song SW, Han P, Cai GJ, Su DF (2010) Effects of low-dose ketanserin on atherosclerosis in rats and rabbits. Can J Physiol Pharmacol 88:1054–1060

    Article  PubMed  CAS  Google Scholar 

  26. Shen FM, Zhang SH, Xie HH, Jing Q, Wang DS, Su DF (2006) Early structural changes of aortic wall in sinoaortic-denervated rats. Clin Exp Pharmacol Physiol 33:358–363

    Article  PubMed  CAS  Google Scholar 

  27. Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H (2009) Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem 146:623–626

    Article  PubMed  CAS  Google Scholar 

  28. Köhn C, Schleifenbaum J, Szijártó IA, Markó L, Dubrovska G, Huang Y, Gollasch M (2012) Differential effects of cystathionine-γ-lyase-dependent vasodilatory H(2)S in periadventitial vasoregulation of rat and mouse aortas. PLoS ONE 7:e41951

    Article  PubMed  Google Scholar 

  29. Vacek TP, Gillespie W, Tyagi N, Vacek JC, Tyagi SC (2010) Hydrogen sulfide protects against vascular remodeling from endothelial damage. Amino Acids 39:1161–1169

    Article  PubMed  CAS  Google Scholar 

  30. Yang G, Wu L, Bryan S, Khaper N, Mani S, Wang R (2010) Cystathionine gamma-lyase deficiency and overproliferation of smooth muscle cells. Cardiovasc Res 86:487–495

    Article  PubMed  CAS  Google Scholar 

  31. Zhao X, Zhang LK, Zhang CY, Zeng XJ, Yan H, Jin HF, Tang CS, Du JB (2008) Regulatory effect of hydrogen sulfide on vascular collagen content in spontaneously hypertensive rats. Hypertens Res 31:1619–1630

    Article  PubMed  CAS  Google Scholar 

  32. Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R (2008) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 322:587–590

    Article  PubMed  CAS  Google Scholar 

  33. Gerová M, Kristek F (2001) Efficiency of NO donors in substituting the impaired endogenous NO production: functional and morphological study. Physiol Res 50:165–173

    PubMed  Google Scholar 

  34. Sarkar R, Meinberg EG, Stanley JC, Gordon D, Webb RC (1996) Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res 78:225–230

    Article  PubMed  CAS  Google Scholar 

  35. Graham DA, Rush JW (2004) Exercise training improves aortic endothelium-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertensive rats. J Appl Physiol 96:2088–2096

    Article  PubMed  CAS  Google Scholar 

  36. Li XH, Peng J, Tan N, Wu WH, Li TT, Shi RZ, Li YJ (2010) Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension. Vascul Pharmacol 53:223–229

    Article  PubMed  CAS  Google Scholar 

  37. Tain YL, Huang LT, Lin IC, Lau YT, Lin CY (2010) Melatonin prevents hypertension and increased asymmetric dimethylarginine in young spontaneous hypertensive rats. J Pineal Res 49:390–398

    Article  PubMed  CAS  Google Scholar 

  38. Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R, Vallance P (2003) Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol 23:1455–1459

    Article  PubMed  CAS  Google Scholar 

  39. Kimura H, Kon N, Furukawa S, Mukaida M, Yamakura F, Matsumoto K, Sone H, Murakami-Murofushi K (2010) Effect of endurance exercise training on oxidative stress in spontaneously hypertensive rats (SHR) after emergence of hypertension. Clin Exp Hypertens 32:407–415

    Article  PubMed  CAS  Google Scholar 

  40. Touyz RM, Schiffrin EL (2004) Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 122:339–352

    Article  PubMed  CAS  Google Scholar 

  41. Carballala S, Trujillob M, Cuevasantaa E, Bartesaghib S, Möllerc MN, Folkesf LK, García-Bereguiaíng MA, Gutiérrez-Merinog C, Wardmanf P, Denicolac A, Radib R, Alvarez B (2011) Reactivity of hydrogen sulfide with peroxynitrite and other oxidants of biological interest. Free Radic Biol Med 50:196–205

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Physical Education, Xi’an Technological University, Xi’an, 4 Jinhua Road, Xi’an, 710032, Shaanxi Province, China

    Qi Gu & Bing Wang

  2. Department of Gynecology, Chengyang People’s Hospital, Qingdao, Shandong Province, China

    Xiao-Feng Zhang

  3. Department of Neurology, Chengyang People’s Hospital, Qingdao, Shandong Province, China

    Yan-Ping Ma

  4. Department of Gastroenterology, The Third People’s Hospital of Datong, Datong, Shanxi Province, China

    Jian-Dong Liu

  5. Department of General Surgery, Yuquan Hospital of Tsinghua University, Beijing, China

    Xiao-Ze Wang

Authors
  1. Qi Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Feng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan-Ping Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian-Dong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiao-Ze Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qi Gu.

Additional information

Qi Gu and Bing Wang contributed equally to the work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gu, Q., Wang, B., Zhang, XF. et al. Contribution of hydrogen sulfide and nitric oxide to exercise-induced attenuation of aortic remodeling and improvement of endothelial function in spontaneously hypertensive rats. Mol Cell Biochem 375, 199–206 (2013). https://doi.org/10.1007/s11010-012-1542-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-012-1542-1

Keywords

Search

Navigation