Apelin Is a Negative Regulator of Angiotensin II-Mediated Adverse Myocardial Remodeling and Dysfunction

Zhen-Zhou Zhang; Wang Wang; Hai-Yan Jin; Xueyi Chen; Yu-Wen Cheng; Ying-Le Xu; Bei Song; Josef M Penninger; Gavin Y Oudit; Jiu-Chang Zhong

doi:10.1161/HYPERTENSIONAHA.117.10156

Apelin Is a Negative Regulator of Angiotensin II-Mediated Adverse Myocardial Remodeling and Dysfunction

Hypertension. 2017 Dec;70(6):1165-1175. doi: 10.1161/HYPERTENSIONAHA.117.10156. Epub 2017 Oct 3.

Authors

Affiliations

¹ From the State Key Laboratory of Medical Genomics and Shanghai Institute of Hypertension (Z.-Z.Z., Y.-W.C., Y.-L.X., B.S., J.-C.Z.) and Department of Mental Health (H.-Y.J.), Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China; Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, China (Z.-Z.Z., J.-C.Z.); Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute (W.W., X.C., G.Y.O.) and Department of Physiology (W.W., X.C., G.Y.O.), University of Alberta, Edmonton, Canada; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.).
² From the State Key Laboratory of Medical Genomics and Shanghai Institute of Hypertension (Z.-Z.Z., Y.-W.C., Y.-L.X., B.S., J.-C.Z.) and Department of Mental Health (H.-Y.J.), Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China; Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, China (Z.-Z.Z., J.-C.Z.); Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute (W.W., X.C., G.Y.O.) and Department of Physiology (W.W., X.C., G.Y.O.), University of Alberta, Edmonton, Canada; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (J.M.P.). jiuchangzhong@aliyun.com gavin.oudit@ualberta.ca.

PMID: 28974565
DOI: 10.1161/HYPERTENSIONAHA.117.10156

Abstract

The apelin pathway has emerged as a critical regulator of cardiovascular homeostasis and disease. However, the exact role of pyr1-apelin-13 in angiotensin (Ang) II-mediated heart disease remains unclear. We used apelin-deficient (APLN^-/y) and apolipoprotein E knockout mice to evaluate the regulatory roles of pyr1-apelin-13. The 1-year aged APLN^-/y mice developed myocardial hypertrophy and dysfunction with reduced angiotensin-converting enzyme 2 levels. Ang II infusion (1.5 mg kg^-1 d^-1) for 4 weeks potentiated oxidative stress, pathological hypertrophy, and myocardial fibrosis in young APLN^-/y hearts resulting in exacerbation of cardiac dysfunction. Importantly, daily administration of 100 μg/kg pyr1-apelin-13 resulted in upregulated angiotensin-converting enzyme 2 levels, decreased superoxide production and expression of hypertrophy- and fibrosis-related genes leading to attenuated myocardial hypertrophy, fibrosis, and dysfunction in the Ang II-infused apolipoprotein E knockout mice. In addition, pyr1-apelin-13 treatment largely attenuated Ang II-induced apoptosis and ultrastructural injury in the apolipoprotein E knockout mice by activating Akt and endothelial nitric oxide synthase phosphorylation signaling. In cultured neonatal rat cardiomyocytes and cardiofibroblasts, exposure of Ang II decreased angiotensin-converting enzyme 2 protein and increased superoxide generation, cellular proliferation, and migration, which were rescued by pyr1-apelin-13, and Akt and endothelial nitric oxide synthase agonist stimulation. The increased superoxide generation and apoptosis in cultured cardiofibroblasts in response to Ang II were strikingly prevented by pyr1-apelin-13 which was partially reversed by cotreatment with the Akt inhibitor MK2206. In conclusion, pyr1-apelin-13 peptide pathway is a negative regulator of aging-mediated and Ang II-mediated adverse myocardial remodeling and dysfunction and represents a potential candidate to prevent and treat heart disease.

Keywords: angiotensin II; dysfunction; hypertension; hypertrophy; oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II / toxicity
Animals
Animals, Newborn
Apelin / metabolism*
Apoptosis
Cells, Cultured
Disease Models, Animal
Hypertension / complications
Hypertension / metabolism*
Hypertension / physiopathology
Hypertrophy, Left Ventricular / etiology
Hypertrophy, Left Ventricular / metabolism*
Hypertrophy, Left Ventricular / physiopathology
Male
Mice
Mice, Knockout
Myocytes, Cardiac / metabolism
Myocytes, Cardiac / pathology
Oxidative Stress*
Rats, Sprague-Dawley
Ventricular Remodeling*

Substances

Apelin
Apln protein, mouse
Angiotensin II

Grants and funding

115080/CIHR/Canada