Low Glial Angiotensinogen Improves Body Habitus, Diastolic Function, and Exercise Tolerance in Aging Male Rats

Overview

Journal Cardiovasc Endocrinol

Specialty Cardiology & Vascular Diseases

Date 2013 Jun 25

PMID 23795309

Citations 7

Authors

Leanne Groban

Hao Wang

Frederico S M Machado

Aaron J Trask

Stephen B Kritchevsky

Carlos M Ferrario

Debra I Diz

Affiliations

Soon will be listed here.

Abstract

Objectives: Long-term systemic blockade of the renin-angiotensin system (RAS) with either an angiotensin (Ang) II type 1 receptor antagonist or an angiotensin-converting enzyme inhibitor attenuates age-related cardiac remodeling and oxidative damage, and improves myocardial relaxation. However, the role of the brain RAS in mediating the development of diastolic dysfunction during aging is not known. We hypothesized that low brain RAS protects against the development of age-related diastolic dysfunction and left ventricular remodeling.

Methods: Sixty-week-old transgenic male ASrAOGEN rats ( =9), with normal circulating Ang II and functionally low brain Ang II, because of a GFAP promoter-linked angiotensinogen antisense targeted to glia, and age-matched and sex-matched Hannover Sprague-Dawley (SD; = 9) rats, with normal levels of both circulating and brain Ang II, underwent echocardiograms to evaluate cardiac structure and function. Postmortem hearts were further compared for histological, molecular, and biochemical changes consistent with cardiac aging.

Results: ASrAOGEN rats showed preserved systolic and diastolic function at mid-life and this was associated with a lower, more favorable ratio of the phospholamban-SERCA2 ratio, reduced incidence of histological changes in the left ventricle, and increased cardiac Ang-(1-7) when compared with the in-vivo functional, and ex-vivo structural and biochemical indices from age-matched SD rats. Moreover, ASrAOGEN rats had lower percent body fat and a superior exercise tolerance when compared with SD rats of the same age.

Conclusion: Our data indicate that the central RAS plays a role in the maintenance of diastolic function and exercise tolerance in mid-life and this may be related to effects on body habitus.

Citing Articles

ACE2 activator diminazene aceturate reduces adiposity but preserves lean mass in young and old rats.

Bruce E, Sakarya Y, Kirichenko N, Toklu H, Sumners C, Morgan D Exp Gerontol. 2018; 111:133-140.

PMID: 30006298 PMC: 6410576. DOI: 10.1016/j.exger.2018.07.008.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology.

Forrester S, Booz G, Sigmund C, Coffman T, Kawai T, Rizzo V Physiol Rev. 2018; 98(3):1627-1738.

PMID: 29873596 PMC: 6335102. DOI: 10.1152/physrev.00038.2017.

Integrative Physiological Aspects of Brain RAS in Hypertension.

de Morais S, Shanks J, Zucker I Curr Hypertens Rep. 2018; 20(2):10.

PMID: 29480460 PMC: 6324839. DOI: 10.1007/s11906-018-0810-1.

Effect of Age, Estrogen Status, and Late-Life GPER Activation on Cardiac Structure and Function in the Fischer344×Brown Norway Female Rat.

Alencar A, da Silva J, Lin M, Silva A, Sun X, Ferrario C J Gerontol A Biol Sci Med Sci. 2016; 72(2):152-162.

PMID: 27006078 PMC: 5233906. DOI: 10.1093/gerona/glw045.

The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats.

Winkler M, Schuchard J, Stolting I, Vogt F, Barkhausen J, Thorns C Br J Pharmacol. 2016; 173(10):1602-17.

PMID: 26892671 PMC: 4842920. DOI: 10.1111/bph.13461.

References

Xu J, Carretero O, Liao T, Peng H, Shesely E, Xu J . Local angiotensin II aggravates cardiac remodeling in hypertension. Am J Physiol Heart Circ Physiol. 2010; 299(5):H1328-38. PMC: 2993216. DOI: 10.1152/ajpheart.00538.2010. View

Cuadra A, Shan Z, Sumners C, Raizada M . A current view of brain renin-angiotensin system: Is the (pro)renin receptor the missing link?. Pharmacol Ther. 2009; 125(1):27-38. PMC: 2815255. DOI: 10.1016/j.pharmthera.2009.07.007. View

Nagueh S, Mikati I, Kopelen H, Middleton K, Quinones M, Zoghbi W . Doppler estimation of left ventricular filling pressure in sinus tachycardia. A new application of tissue doppler imaging. Circulation. 1998; 98(16):1644-50. DOI: 10.1161/01.cir.98.16.1644. View

Sakima A, Averill D, Gallagher P, Kasper S, Tommasi E, Ferrario C . Impaired heart rate baroreflex in older rats: role of endogenous angiotensin-(1-7) at the nucleus tractus solitarii. Hypertension. 2005; 46(2):333-40. DOI: 10.1161/01.HYP.0000178157.70142.33. View

Sakima A, Averill D, Kasper S, Jackson L, Ganten D, Ferrario C . Baroreceptor reflex regulation in anesthetized transgenic rats with low glia-derived angiotensinogen. Am J Physiol Heart Circ Physiol. 2006; 292(3):H1412-9. DOI: 10.1152/ajpheart.00984.2006. View

Little W, Zile M, Klein A, Appleton C, Kitzman D, Wesley-Farrington D . Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol. 2006; 98(3):383-5. DOI: 10.1016/j.amjcard.2006.01.106. View

Lakatta E . Similar myocardial effects of aging and hypertension. Eur Heart J. 1990; 11 Suppl G:29-38. DOI: 10.1093/eurheartj/11.suppl_g.29. View

Benter I, Yousif M, Al-Saleh F, Raghupathy R, Chappell M, Diz D . Angiotensin-(1-7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG-nitro-L-arginine methyl ester. J Cardiovasc Pharmacol. 2011; 57(5):559-67. PMC: 3095755. DOI: 10.1097/FJC.0b013e31821324b6. View

Zhao L, Jiang H, Papasian C, Maulik D, Drees B, Hamilton J . Correlation of obesity and osteoporosis: effect of fat mass on the determination of osteoporosis. J Bone Miner Res. 2007; 23(1):17-29. PMC: 2663586. DOI: 10.1359/jbmr.070813. View

10.

Halade G, Rahman M, Williams P, Fernandes G . High fat diet-induced animal model of age-associated obesity and osteoporosis. J Nutr Biochem. 2010; 21(12):1162-9. PMC: 2888860. DOI: 10.1016/j.jnutbio.2009.10.002. View

11.

Diz D, Arnold A, Nautiyal M, Isa K, Shaltout H, Tallant E . Angiotensin peptides and central autonomic regulation. Curr Opin Pharmacol. 2011; 11(2):131-7. PMC: 3120135. DOI: 10.1016/j.coph.2011.02.001. View

12.

Russo C, Jin Z, Homma S, Rundek T, Elkind M, Sacco R . Effect of obesity and overweight on left ventricular diastolic function: a community-based study in an elderly cohort. J Am Coll Cardiol. 2011; 57(12):1368-74. PMC: 3077126. DOI: 10.1016/j.jacc.2010.10.042. View

13.

Wang M, Zhang J, Walker S, Dworakowski R, Lakatta E, Shah A . Involvement of NADPH oxidase in age-associated cardiac remodeling. J Mol Cell Cardiol. 2010; 48(4):765-72. PMC: 2877878. DOI: 10.1016/j.yjmcc.2010.01.006. View

14.

Huang B, Ahmad M, Tan J, Leenen F . Sympathetic hyperactivity and cardiac dysfunction post-MI: different impact of specific CNS versus general AT1 receptor blockade. J Mol Cell Cardiol. 2007; 43(4):479-86. DOI: 10.1016/j.yjmcc.2007.07.047. View

15.

Kasper S, Ferrario C, Ganten D, Diz D . Rats with low brain angiotensinogen do not exhibit insulin resistance during early aging. Endocrine. 2007; 30(2):167-74. DOI: 10.1385/ENDO:30:2:167. View

16.

Arnold A, Shaltout H, Gallagher P, Diz D . Leptin impairs cardiovagal baroreflex function at the level of the solitary tract nucleus. Hypertension. 2009; 54(5):1001-8. PMC: 2789663. DOI: 10.1161/HYPERTENSIONAHA.109.138065. View

17.

Alpert M . Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome. Am J Med Sci. 2001; 321(4):225-36. DOI: 10.1097/00000441-200104000-00003. View

18.

Pascual M, Pascual D, Soria F, Vicente T, Hernandez A, Tebar F . Effects of isolated obesity on systolic and diastolic left ventricular function. Heart. 2003; 89(10):1152-6. PMC: 1767886. DOI: 10.1136/heart.89.10.1152. View

19.

Huang B, Ganten D, Leenen F . Responses to central Na(+) and ouabain are attenuated in transgenic rats deficient in brain angiotensinogen. Hypertension. 2001; 37(2 Pt 2):683-6. DOI: 10.1161/01.hyp.37.2.683. View

20.

Schinke M, Baltatu O, Bohm M, Peters J, Rascher W, Bricca G . Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen. Proc Natl Acad Sci U S A. 1999; 96(7):3975-80. PMC: 22405. DOI: 10.1073/pnas.96.7.3975. View