Pyr1-Apelin 13 is a negative modulator of angiotensin II-mediated adverse myocardial hypertrophy, remodeling and fibrosis
Jiuchang ZHONG1 Zhenzhou Zhang1 Haiyan Jin1 Wang Wang2 Yuwen Cheng1 Xueyi Chen2 Yingle Xu1 Bei Song1 Josef M Penninger3 Gavin Y Oudit2 Jiuchang Zhong1
1.State Key Laboratory of Medical Genomics, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension
2.Division of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute
3.Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Objectives: The apelin (APLN)/APJ receptor system and angiotensin (Ang) II-Ang II type 1 receptor (AT1) pathways have emerged as potent regulators of blood pressure and cardiovascular function. The beneficial effects of the APLN/APJ receptor system are well-established in diverse conditions such as hypertension, atherosclerosis, and heart failure. However, little was elucidated upon the interaction between the APLN/APJ receptor and Ang II-AT1 signaling in heart disease. Here, we examined the regulatory role of pyr1-apelin-13 in the atherosclerosis-prone apolipoprotein E (ApoE) knockout (KO) mice in response to Ang II.
Methods: The male 10-week aged male WT, APLN-/y and ApoEKO mice were randomized to deliver either Ang II (1.5 mg.kg-1.d-1) or saline with an osmotic minipump for 4-weeks. To evaluate myocardial fibrosis, Masson’s Trichrome and Picrosirius Red staining was performed. Transmission electron microscope analysis of left ventricular samples was carried out using a conventional scanning transmission electron microscope.
Results: Gross histology data demonstrated normal morphology between young WT and APLN-/y mice. Intriguingly, loss of APLN resulted in greater myocardial hypertrophy and remodeling in Ang II-treated APLN-/y mice. Loss of apelin potentiated Ang II-induced perivascular and interstitial myocardial fibrosis and transcriptional activation of pro-fibrotic mediators resulting in great accumulation of collagen I and collagen III in APLN-/y hearts. In ApoEKO mice, myocardial hypertrophy was increased based on morphological characterization with equivalent pressor response compared with WT mice in response to Ang II. These changes resulted in increased myocardial fibrosis in the Ang II-infused ApoEKO mice. Pyr1-apelin-13 treatment prevented Ang II-mediated hypertrophy and fibrosis in both WT and ApoEKO mice, along with decreased myocardial mRNA expression of ANF, BNP, b-MHC, collagen I and collagen III. Ang II-induced altered myocardial ultrastructure characterized by disruption or dissolution of myocardial myofilaments, vacuolar degeneration and swollen mitochondria were aggravated in the ApoEKO mice which were prevented by pyr1-apelin-13.
Conclusions: Loss of APLN exacerbates Ang II-mediated cardiac hypertrophy and fibrosis. The APLN/APJ pathway has a protective role against Ang II-mediated heart disease and pyr1-apelin-13 mediates therapeutic effects in ApoE-mutant mice.These findingshighlight the importance of enhancing APLN/APJ action as a novel therapeutic target for heart disease. This work was supported by the National Natural Science Foundation of China (81370362), the National Basic Research Program of China (2014CB542300) and the National Major Research Plan (91339108).