Cardiac remodeling includes changes to both cardiomyocytes and cardiac fibroblasts as well as vascular smooth muscle cells (VSMCs) and perivascular fibroblasts of intracoronary arteries which occur in response to injury to the heart concomitant with hypertension, myocardial infarction, or aging. These alterations, due to both hemodynamic and humoral factors such as angiotensin II (Ang II) and endothelin (Et-1), result in left ventricular hypertrophy, coronary artery thickening as well as perivascular and interstitial fibrosis. Angiotensin- (1-7) [Ang-(1-7)] is an anti-proliferative and anti-fibrotic peptide which opposes the mitogenic, pro-fibrotic effects of various mitogens and hormones including Ang II. During the current funding cycle of Project 2, we showed that Ang-(1-7) inhibits the growth of cardiac myocytes through activation of the G protein-coupled receptor mas and inhibition of the phosphorylation/activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2. The heptapeptide reduces proliferation and decreases collagen synthesis in cardiac fibroblasts, concomitant with up-regulation of the MAP kinase phosphatase DUSP1 and down-regulation of cyclooxygenase-2 (COX-2) and prostaglandin E synthase (PGES-1). Ang-(1-7) also increases DUSP1 in VSMCs, to attenuate ERK1/ERK2 activities, inhibit VSMC growth, and reduce vascular hypertrophy and perivascular fibrosis. Based upon these observations, the hypothesis of this project is that Ang-(1-7) counterregulates the effects of Ang II by up-regulating the MAP kinase phosphatase DUSP1 to prevent hypertrophy and reduce fibrosis. Preliminary studies show that administration of Ang-(1-7) to normotensive rats chronically treated with Ang II causes a pressure-independent reduction in the interstitial and perivascular fibrosis and coronary artery hypertrophy associated with cardiac remodeling. We will use this model to identify the molecular mechanisms by which Ang-(1-7) inhibits cell growth and fibrosis, using a combination of molecular biology, proteonomic and immunocytochemical techniques. The role of the protein phosphatase DUSP1 in hypertrophy and fibrosis will be studied in normotensive rats transfected with lentivirus containing shRNAs to the MAP kinase phosphatase DUSP1 to reduce or ablate the enzyme in vivo and attenuate the response to Ang-(1-7) treatment. The role of Ang-(1-7) in preventing the Ang ll-mediated inflammatory response by reducing cyclooxygenase 2 (COX-2) activity or prostaglandin synthase activities to alter the ratio of proliferative to anti-proliferative prostanoids will be determined in vitro and in vivo, in cultured cells and tissues from rats treated with angiotensin peptides. Finally, hypertensive rats of the mRen2.Lewis congenic strain, normotensive rats with ischemia/reperfusion injury and aged rats with progressive heart disease will be treated with Ang-(1-7), in preclinical studies to demonstrate the efficacy of Ang-(1-7) in reducing cardiac hypertrophy and fibrosis. Ang-(1-7) may represent a novel targeted therapeutic treatment for cardiac pathologies associated with high blood pressure, myocardial infarction, and aging.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
United States
Zip Code
Cohall, Damian H; Scantlebury-Manning, Thea; James, Stephen et al. (2015) Renin-angiotensin-aldosterone system gender differences in an Afro-Caribbean population. J Renin Angiotensin Aldosterone Syst 16:539-46
Ahmad, Sarfaraz; Varagic, Jasmina; Groban, Leanne et al. (2014) Angiotensin-(1-12): a chymase-mediated cellular angiotensin II substrate. Curr Hypertens Rep 16:429
Marshall, Allyson C; Pirro, Nancy T; Rose, James C et al. (2014) Evidence for an angiotensin-(1-7) neuropeptidase expressed in the brain medulla and CSF of sheep. J Neurochem 130:313-23
Varagic, Jasmina; Ahmad, Sarfaraz; Nagata, Sayaka et al. (2014) ACE2: angiotensin II/angiotensin-(1-7) balance in cardiac and renal injury. Curr Hypertens Rep 16:420
Ferrario, Carlos Maria; Ahmad, Sarfaraz; Nagata, Sayaka et al. (2014) An evolving story of angiotensin-II-forming pathways in rodents and humans. Clin Sci (Lond) 126:461-9
Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T et al. (2014) Enhanced activity of an angiotensin-(1-7) neuropeptidase in glucocorticoid-induced fetal programming. Peptides 52:74-81
Lindsey, Sarah H; Liu, Liu; Chappell, Mark C (2014) Vasodilation by GPER in mesenteric arteries involves both endothelial nitric oxide and smooth muscle cAMP signaling. Steroids 81:99-102
Moniwa, Norihito; Varagic, Jasmina; Ahmad, Sarfaraz et al. (2013) Hemodynamic and hormonal changes to dual renin-angiotensin system inhibition in experimental hypertension. Hypertension 61:417-24
Moniwa, Norihito; Varagic, Jasmina; Simington, Stephen W et al. (2013) Primacy of angiotensin converting enzyme in angiotensin-(1-12) metabolism. Am J Physiol Heart Circ Physiol 305:H644-50
Lindsey, Sarah H; da Silva, Ariel S; Silva, Mauro S et al. (2013) Reduced vasorelaxation to estradiol and G-1 in aged female and adult male rats is associated with GPR30 downregulation. Am J Physiol Endocrinol Metab 305:E113-8

Showing the most recent 10 out of 229 publications