Apelin Is a Negative Regulator of Angiotensin II–Mediated Adverse Myocardial Remodeling and Dysfunction. Issue 6 (December 2017)

• Record Type: Journal Article
• Authors: Zhang, Zhen-Zhou; Wang, Wang; Jin, Hai-Yan; Chen, Xueyi; Cheng, Yu-Wen; Xu, Ying-Le; Song, Bei; Penninger, Josef M.; Oudit, Gavin Y.; Zhong, Jiu-Chang
• Is Part Of: Hypertension. Volume 70:Issue 6(2017:Dec.)
• Publication Date: 2017-12
• Subjects: angiotensin II -- dysfunction -- hypertension -- hypertrophy -- oxidative stress; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.117.10156
• Languages: English
• ISSNs: 0194-911X

Abstract

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. Abstract : Supplemental Digital Content is available in the text.