Intermedin(1-53) Protects Against Myocardial Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Inflammation Induced by Homocysteine in Apolipoprotein E-Deficient Mice

Aim: Endoplasmic reticulum stress (ERS) and inflammation participate in cardiac fibrosis. Importantly, a novel paracrine/autocrine peptide intermedin(1-53) (IMD1-53) in the heart inhibits myocardial fibrosis in rats. However, the mechanisms are yet to be fully elucidated. Methods: Myocardial fibrosis in apolipoprotein E-deficient (ApoE(-/-)) mice and neonatal rat cardiac fibroblasts (CFs) were induced using homocysteine (Hcy). Results: IMD1-53 inhibited myocardial fibrosis in vivo and in vitro. Picrosirius red staining showed that IMD1-53 reduced myocardial interstitial collagen deposition in ApoE(-/-)mice treated with Hcy and decreased the expression of myocardial collagen I and III , which was further verified in rat CFs. IMD1-53 attenuated myocardial hypertrophy, as shown by cardiomyocyte cross-sectional area, ratio of heart weight to body weight, and mRNA levels of atrial natriuretic peptide and brain natriuretic peptide. IMD1-53 inhibited the upregulation of ERS hallmarkers such as glucose-regulated protein 78 (GRP78), GRP94, activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1 alpha, spliced-X-box-binding protein-1, protein kinase receptor-like ER kinase, and eukaryotic translation initiation factor 2 alpha in mouse myocardium and rat CFs treated with Hcy. In addition, IMD1-53 decreased the production of inflammatory factors such as tumor necrosis factor-alpha, monocyte chemotactic protein-1, interleukin-6 (IL-6), and IL-1 beta in the mouse myocardium and rat CFs treated with Hcy. Concurrently, IMD1-53 ameliorated the expression of nuclear factor-kappa B, transforming growth factor-beta 1, and c-Jun N-terminal kinase in the mouse myocardium and rat CFs treated with Hcy. Conclusions: IMD potentially protects against myocardial fibrosis induced by Hcy in ApoE(-/-) mice, possibly via attenuating myocardial ERS and inflammation.National Natural Science Foundation of China [81170082, 91339203, 81670434, 81270407]SCI(E)PubMedARTICLEyongfenqi@163.com111294-13062