Skip to main content
Intended for healthcare professionals
Free access
Research article
First published online May 9, 2011

Beneficial effects of angiotensin (1–7) in diabetic rats with cardiomyopathy

Abstract

Objective: This study was designed to investigate the effect of angiotensin (1–7), a Mas receptor agonist, and A-779, a Mas receptor antagonist, in rats with diabetic cardiomyopathy (DC).
Methods: Rats treated with a single injection of streptozotocin (50 mg/kg, intraperitoneal), developed DC after 8 weeks. The extent of DC was assessed by measuring the left ventricular weight/body weight (LVW/BW) ratio, absolute LVW, left ventricular developed pressure (LVDP), maximum change in left ventricular pressure over time (dp/dtmax), minimum change in left ventricular pressure over time (dp/dtmin), left ventricular (LV) protein content, LV collagen content, lipid profile, and serum nitrite/nitrate concentration. Test drug treatment was given from week 4 to week 8.
Results: Angiotensin (1–7) treatment attenuated DC by significantly increasing LVDP, dp/dtmax, dp/dtmin, serum nitrite/nitrate concentration and significantly decreasing the LVW/BW ratio and LV collagen content. For the first time, this study has documented that endogenous angiotensin (1–7) regulates lipid profile in rats, and that treatment with angiotensin (1–7) significantly attenuates diabetes-induced changes in lipid profile. However, LV protein content and absolute LVW remain unaffected after treatment.
Conclusion: Angiotensin (1–7) significantly attenuates DC in rats because of vasodilatory, antiproliferative and anifibrotic properties but also because of a significant decrease in dyslipidemia, the major culprit for cardiac dysfunctions in diabetes.

References

Allain C.C., Poon L.S., Chan C.S.G., Richmond W., Fu P.C. (1974) Enzymatic determination of total serum cholesterol. Clin Chem 20: 470–475.
Al-Maghrebi M., Benter I.F., Diz D.I. (2009) Endogenous angiotensin-(1–7) reduces cardiac ischemia-induced dysfunction in diabetic hypertensive rats. Pharmacol Res 59: 263–268.
Benter I.F., Yousif M.H., Anim J.T., Cojocel C., Diz D.I. (2006) Angiotensin-(1–7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME. Am J Physiol 290: H684–H691.
Benter I.F., Yousif H.M., Anim J.T., Cojocel C., Diz D.I. (2007) Angiotensin-(1–7) prevents diabetes-induced cardiovascular dysfunction. Am J Physiol Heart Circ Physiol 292: H666–H672.
Brenner B.M., Cooper M.E., DeZeeuw D., Keane W.F., Mitch W.E., Parving H.H., et al. (2001) Effect of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Eng J Med 345: 861–869.
Brownlee M. (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54: 1615–1625.
Castro C.H., Santos R.A., Ferreira A.J., Bader M., Alenina N., Almeida A.P. (2006) Effects of genetic deletion of angiotensin-(1–7) receptor Mas on cardiac function during ischemia/reperfusion in the isolated perfused mouse heart. Life Sci 80: 264–268.
Cheng L., Ding G., Qin Q., Huang Y., Lewis W., He N., et al. (2004) Cardiomyocyte-restricted peroxisome proliferatoractivated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 10: 1245–1250.
Chiu H.C., Kovacs A., Blanton R.M., Han X., Courtois M., Weinheimer C.J., et al. (2005) Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Cir Res 96: 225–233.
Cho B.H.S. (1983) Improved enzymatic determination of total cholesterol in tissues. Clin Chem 29: 166–168.
Crackower M.A., Sarao R., Oudit G.Y., Yagil C., Kozieradzki I., Scanga S.E., et al. (2002) Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417: 822–828.
Deepa P.R., Varalakshmi P. (2005) Beneficial cardio-renovascular effects of low-molecular-weight heparin-derivative on adriamycin-induced glycosaminoglycanuria and tissue lipid abnormalities. Toxicology 211: 77–85.
Devereux R.B., Roman M.J., Paranicas M. (2000) Impact of diabetes on cardiac structure and functions: The strong heart study. Circulation 101: 2271–2276.
Dirk W., Susanne R., Sebastian J., Anne L., Stefan A., Alexander R., et al. (2007) Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy. Diabetes 56: 641–646.
Donoghue M., Hsieh F., Baronas E., Godbout K., Gosselin M., Stagliano N., et al. (2000) A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Cir Res 87: E1–E9.
Ferrario C.M., Jessup J., Chappell M.C., Averill D.B., Brosnihan K.B., Tallant E.A., et al. (2005a) Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 111: 2605–2610.
Ferrario C.M., Jessup J., Gallagher P.E., Averill D.B., Brosnihan K.B., AnnTallant E., et al. (2005b) Effects of rennin–angiotensin system blockade on renal angiotensin-(1–7) forming enzymes and receptors. Kidney Int 68: 2189–2196.
Ferreira A.J., Santos R.A. (2005) Cardiovascular actions of angiotensin-(1–7). Braz J Med Biol Res 38: 499–507.
Ferreira A.J., Santos R.A.S., Almeida A.P. (2002) Angiotensin-(1–7) improves the post- ischemic function in isolated perfused rat hearts. Braz J Med Biol Res 35: 1083–1090.
Finck B.N., Han X., Courtois M., Aimond F., Nerbonne J.M., Kovacs A., et al. (2003) A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci U S A 100: 1226–1231.
Folch J., Lees M., Sloane-Stanley G.H. (1957) A simple method for isolation and purification of total lipids from animal tissue. J Biol Chem 226: 497–509.
Giani J.F., Gironacci M.M., Munoz M.C., Pena C., Daniel T., Dominici F.P. (2007) Angiotensin-(1–7) stimulates the phosphorylation of JNK2, IRS-1 and Akt in rat heart in vivo: role of AT1 and Mas receptors. Am J Physiol Heart Circ Physiol 293: H1154–H1163.
Giani J.F., Muñoz M.C., Mayer M.A., Veiras L.C., Arranz C., Taira C.A., et al. (2010) Angiotensin-(1–7) improves cardiac remodeling and inhibits growth-promoting pathways in the heart of fructose-fed rats. Am J Physiol Heart Circ Physiol 298: H1003–H1013.
Gurley S.B., Allred A., Le T.H., Griffiths R., Mao L., Philip N., et al. (2006) Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest 116: 2218–2225.
Hamblin M., Frieddman D.B., Hill S., Richard M.C., Smith H.M., Hill M.S. (2007) Altrations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy. J Mol Cell Cardiol 42: 884–895.
Harmer D., Gilbert M., Borman R., Clark K.L. (2002) Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett 532: 107–110.
Herrero P., Peterson L.R., McGill J.B., Matthew S., Lesniak D., Dence C., et al. (2006) Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J Am Coll Cardiol 47: 598–604.
Iwata M., Cowling R.T., Gurantz D., Moore C., Zhang S., Yuan J.X.J., et al. (2005) Angiotensin-(1–7) binds to specific receptors on cardiac fibroblasts to initiate anti-fibrotic and anti-trophic effects. Am J Physiol 289: H2356–H2363.
Jamall I.S., Finelli V.N., Que Hee S.S. (1981) A simple method to determine nanogram levels of 4-hydroxyproline in biological tissues. Anal Biochem 112: 70–75.
Jayasooria A.P., Mathai M.L., Walker L.L., Begg D.P., Denton D.A., Cameron-Smith D., et al. (2008) Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance. Proc Natl Acad Sci U S A 105: 6531–6536.
Leehey D.J., Singh A.K., Bast J.P., Singh R. (2008) Glomerular renin angiotensin system in streptozotocin diabetic and Zucker diabetic fatty rats. Transl Res 151: 208–216.
Lowry O.H., Rosenberg A.L.F., Randall R.J. (1951) Protein measurement with folin phenol reagent. J Biol Chem 193: 265–275.
Miller J.A., Floras J.S., Zinman B., Skorecki K.L., Logan A.G. (1996) Effect of hyperglycaemia on arterial pressure, plasma renin activity and renal function in early diabetes. Clin Sci 90: 189–195.
Nielsen L.B., Bartels E.D., Bollano E. (2002) Overexpression of apolipoprotein B in the heart impedes cardiac triglyceride accumulation and development of cardiac dysfunction in diabetic mice. J Biol Chem 277: 27014–27020.
Poornima I.J., Parikh P., Shannon R.P. (2006) Diabetic cardiomyopathy: the search for unifying hypothesis. Circ Res 98: 596–605.
Ruggenenti P., Mise N., Pisoni R., Arnoldi F., Pezzotta A., Perna A., et al. (2003) Diverse effects of increasing lisinopril doses on lipid abnormalities in chronic nephropathies. Circulation 107: 586–592.
Sajad A.H., Billal P., Rajdeep S.K., Rayaz A.M. (2004) Diabetic cardiomyopathy: mechanisms, diagnosis and treatment. Clin Sci 107: 539–557.
Sampaio W.O., Santos R.A.S., Faria-Silva R., Machado L.T.M., Schiffrin E.L., Touyz R.M. (2007) Angiotensin (1–7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependant pathways. Hypertension 49: 85–192.
Santos R.A., Simões A.C., Maric C. (2003) Angiotensin (1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A 100: 8258–8263.
Sastry K.V.H., Moudgal R.P., Mohan J., Tyagi J.S., Rao G.S. (2002) Spectrophotometric determination of serum nitrite and nitrate by copper–cadmium alloy. Analytical Biochemistry 306: 79–82.
Singh K., Singh T., Sharma P.L. (2010a) Angiotensin (1–7)/Mas receptor axis activation ameliorates the changes in fatty acid composition in diabetic rats with nephropathy. J Exp Pharmacol 2: 163–168.
Singh R., Singh A.K., Leehey D.J. (2005) A novel mechanism for angiotensin II formation in STZ-diabetic rat glomeruli. Am J Physiol Renal Physiol 288: F1183–F1190.
Singh T., Singh K., Sharma P.L. (2010b) Ameliorative potential of angiotensin1–7/Mas receptor axis in streptozotocin-induced diabetic nephropathy in rats. Methods Find Exp Clin Pharmacol 32: 19–25.
Tikellis C., Johnston C.I., Forbes J.M., Burns W.C., Louise M., Risvanis B.J., et al. (2003) Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy. Hypertension 41: 392–397.
Tipnis S.R., Hooper N.M., Hyde R., Karran E., Christie G., Turner A.J. (2000) A human homolog of angiotensin converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275: 33238–33243.
Trinder P. (1969) Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 6: 24–25.
Vickers C., Hales P., Kaushik V., Dick L., Gavin J., Tang J., et al. (2002) Hydrolysis of biological peptides by human angiotensin converting enzyme-related carboxypeptidase. J Biol Chem 277: 14838–14843.
Wang J., Ye S., Wang Q., Kralik P.M., Epstein P.N. (2006) Causes and characteristics of diabetic cardiomyopathy. Rev Diabet Stud 3: 108–117.
Weisinger R.S., Stanley T.K., Begg D.P., Weisinger H.S., Spark K.J., Jois M. (2009) Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6 J mice maintained on a high fat diet. Physiol Behav 98: 192–197.
Welches W.R., Brosnihan K.B., Ferrario C.M. (1993) A comparison of the properties and enzymatic activities of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase. Life Sci 52: 1461–1480.
Ye M., Wysocki J., Naaz P., Salabat M.S., Batlle D. (2004) Increased ACE 2 and decreased ACE protein in renal tubules from diabetic mice. A renoprotective combination? Hypertension 43: 1120–1125.

Cite article

Cite article

Cite article

OR

Download to reference manager

If you have citation software installed, you can download article citation data to the citation manager of your choice

Share options

Share

Share this article

Share with email
EMAIL ARTICLE LINK
Share on social media

Share access to this article

Sharing links are not relevant where the article is open access and not available if you do not have a subscription.

For more information view the Sage Journals article sharing page.

Information, rights and permissions

Information

Published In

Article first published online: May 9, 2011
Issue published: June 2011

Keywords

  1. A-779
  2. angiotensin (1–7)
  3. diabetic cardiomyopathy
  4. lipids
  5. Mas receptor

Rights and permissions

© The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav.
Request permissions for this article.
PubMed: 21558085

Authors

Affiliations

Kulwinder Singh
Assistant Professor, Department of Pharmacology, ISF College of Pharmacy, Moga, India
Tajinder Singh
Department of Pharmacology, ISF College of Pharmacy, Moga, India
P. L. Sharma
Professor Emeritus, Department of Pharmacology, ISF College of Pharmacy, Moga 142 001, India

Notes

Metrics and citations

Metrics

Journals metrics

This article was published in Therapeutic Advances in Cardiovascular Disease.

VIEW ALL JOURNAL METRICS

Article usage*

Total views and downloads: 304

*Article usage tracking started in December 2016


Altmetric

See the impact this article is making through the number of times it’s been read, and the Altmetric Score.
Learn more about the Altmetric Scores



Articles citing this one

Receive email alerts when this article is cited

Web of Science: 0

Crossref: 23

  1. Renin Angiotensin System in the Pathophysiology of Diabetic Cardiomyop...
    Go to citation Crossref Google Scholar
  2. Activation of angiotensin-converting enzyme 2 ameliorates metabolic sy...
    Go to citation Crossref Google Scholar
  3. Understanding diabetes-induced cardiomyopathy from the perspective of ...
    Go to citation Crossref Google Scholar
  4. ACE2 and energy metabolism: the connection between COVID-19 and chroni...
    Go to citation Crossref Google Scholar
  5. The role of SARS‐CoV‐2 target ACE2 in cardiovascular diseases
    Go to citation Crossref Google Scholar
  6. Angiotensin-(1–7) Expressed From Lactobacillus Bacteria Protect Diabet...
    Go to citation Crossref Google Scholar
  7. The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: F...
    Go to citation Crossref Google Scholar
  8. The Renin Angiotensin System and Diabetes
    Go to citation Crossref Google Scholar
  9. New agents modulating the renin-angiotensin-aldosterone system—Will th...
    Go to citation Crossref Google Scholar
  10. Update on RAAS Modulation for the Treatment of Diabetic Cardiovascular...
    Go to citation Crossref Google Scholar
  11. Angiotensin‐(1–7) administration benefits cardiac, renal and progenito...
    Go to citation Crossref Google Scholar
  12. Angiotensin-(1–7) treatment mitigates right ventricular fibrosis as a ...
    Go to citation Crossref Google Scholar
  13. Neuropeptides: Metabolism to Bioactive Fragments and the Pharmacology ...
    Go to citation Crossref Google Scholar
  14. Metabolic Role of Angiotensin-(1-7)/Mas Axis
    Go to citation Crossref Google Scholar
  15. Modulation of the action of insulin by angiotensin-(1–7)
    Go to citation Crossref Google Scholar
  16. Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascu...
    Go to citation Crossref Google Scholar
  17. Ang (1–7) Protects Islet Endothelial Cells from Palmitate-Induced Apop...
    Go to citation Crossref Google Scholar
  18. Association of Plasma Angiotensin-(1–7) Level and Left Ventricular Fun...
    Go to citation Crossref Google Scholar
  19. Angiotensin-(1–7): beyond the cardio-renal actions
    Go to citation Crossref Google Scholar
  20. Effect of combination of renin inhibitor and Mas-receptor agonist in D...
    Go to citation Crossref Google Scholar
  21. Possible mechanism of the cardio-renal protective effects of AVE-0991,...
    Go to citation Crossref Google ScholarPub Med
  22. Angiotensin-(1–7) in kidney disease: a review of the controversies
    Go to citation Crossref Google Scholar
  23. Review article: the pathophysiological roles of the renin–angiotensin ...
    Go to citation Crossref Google Scholar

Figures and tables

Figures & Media

Tables

View Options

View options

PDF/ePub

View PDF/ePub

Get access

Access options

If you have access to journal content via a personal subscription, university, library, employer or society, select from the options below:


Alternatively, view purchase options below:

Purchase 24 hour online access to view and download content.

Access journal content via a DeepDyve subscription or find out more about this option.