Intermedin_1–53 Protects Against Myocardial Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Inflammation Induced by Homocysteine in Apolipoprotein E-Deficient Mice

Abstract

Aim: Endoplasmic reticulum stress (ERS) and inflammation participate in cardiac fibrosis. Importantly, a novel paracrine/autocrine peptide intermedin1–53 (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 1α, spliced-X-box-binding protein-1, protein kinase receptor-like ER kinase, and eukaryotic translation initiation factor 2α in mouse myocardium and rat CFs treated with Hcy. In addition, IMD1–53 decreased the production of inflammatory factors such as tumor necrosis factor-α, monocyte chemotactic protein-1, interleukin-6 (IL-6), and IL-1β in the mouse myocardium and rat CFs treated with Hcy. Concurrently, IMD1–53 ameliorated the expression of nuclear factor-κB, transforming growth factor-β1, 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.

Intermedin1-53 attenuates aging-associated vascular calcification in rats by upregulating sirtuin 1

“…We showed that in calcified-senescent VSMCs, the levels of p-AMPK and p-Akt were downregulated as compared with control, but the level of p-PKA was upregulated. According to the previous studies, the activation of PKA during aging-associated calcification may be a compensatory protective effect [44,45]. Here, we found that inhibitors of all these three signaling factors -PI3K inhibitor LY294002, AMPK inhibitor Compound C and PKA inhibitor H89 efficiently blocked the upregulation of sirt1 by IMD1-53 and thus inhibited the effects of IMD1-53 on calcium deposition and β-galactosidase activity.…”

Exogenous Pancreatic Kallikrein Improves Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetes

“… Saklani et al (2016) suggested that TNF-α is essential for DCM. IL-6, CD68, and MCP-1 are also important factors in cardiac inflammation ( Guo et al, 2016 ; Zhang J.S. et al, 2016 ).…”

Total Saponins of Aralia Elata (Miq) Seem Alleviate Calcium Homeostasis Imbalance and Endoplasmic Reticulum Stress-Related Apoptosis Induced by Myocardial Ischemia/Reperfusion Injury

“…After treatment with AS (25, 50, 100 mg/kg/day), pathological changes could be reduced to a certain extent, but the lesion was inevitable in Fig. 3, which showed that AS could protect the myocardium from IR injure [17]. In masson staining, the normal cardiac myocytes were stained red and fibrotic areas were stained blue.…”