Biochemistry and Molecular Mechanism Laboratory, Agroprocessing and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology (NIIST), Thiruvananthapuram, Kerala, 695019, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Small Animal Research Facility, Jubilee Centre for Medical Research (JCMR), Jubilee Mission Medical College and Research Institute (JMMCRI), Thrissur, Kerala, 680005, India.
Chem Biol Interact. 2022 Jan 5;351:109755. doi: 10.1016/j.cbi.2021.109755. Epub 2021 Nov 19.
Endoplasmic reticulum (ER) and associated signaling pathways are involved in diabetic cardiomyopathy (DCM) however, detailed studies are not available. The present study investigated the role of ER stress and related pathways such as ER-phagy, apoptosis and their underlying mechanisms using appropriate models. Beneficial effect of chlorogenic acid was also evaluated against ER stress mediated DCM. H9c2 cells with high glucose (33 mM, in vitro model of hyperglycemia) showed significant activation of ER stress response (GRP78, PERK, IRE1α, ATF6α) and altered its regulatory proteins (PDI, ERO1α). Also, it enhanced ER-phagy through upregulation of Sec62, RTN3 and downregulation of FAM134B. High glucose caused apoptosis via increased levels of CHOP, caspase 12 and calnexin. All these proteins (PERK, IRE1α, ATF6α, RTN3, Sec62 and FAM134B) have been found to have a significant role in the functioning of heart such as excitation contraction coupling and we expect these alterations to induce cardiomyopathy during diabetes. This was confirmed in in vivo study too. High fat, high fructose diet with mild streptozotocin induced diabetic rats showed an increased expression of BNP confirming cardiac injury. We also noticed severe ER stress in the heart of diabetic animals. All these have contributed significantly into alterations in histopathology and increase of weight of the hearts. These findings clearly show that ER stress plays a vital protagonist in the progression of DCM. We also found chlorogenic acid is effective against hyperglycemia induced pathological alteration both in vitro as well as in vivo.
内质网（ER）及其相关信号通路参与糖尿病心肌病（DCM），然而，详细的研究尚未开展。本研究采用适当的模型，探讨了 ER 应激及相关途径（如 ER 自噬、细胞凋亡）的作用及其潜在机制。同时还评估了绿原酸对 ER 应激介导的 DCM 的有益作用。高糖（33mM，体外高血糖模型）作用下的 H9c2 细胞显示出 ER 应激反应（GRP78、PERK、IRE1α、ATF6α）的显著激活，并改变了其调节蛋白（PDI、ERO1α）。此外，它通过上调 Sec62、RTN3 和下调 FAM134B 增强 ER 自噬。高糖通过增加 CHOP、caspase 12 和钙连蛋白的水平引起细胞凋亡。所有这些蛋白（PERK、IRE1α、ATF6α、RTN3、Sec62 和 FAM134B）在心脏的功能中都具有重要作用，如兴奋-收缩偶联，我们预计这些改变会在糖尿病期间引起心肌病。这在体内研究中也得到了证实。高脂肪、高果糖饮食联合轻度链脲佐菌素诱导的糖尿病大鼠，其 BNP 的表达增加，证实了心脏损伤。我们还注意到糖尿病动物心脏的 ER 应激严重。所有这些都显著改变了组织病理学和心脏重量的增加。这些发现清楚地表明，ER 应激在 DCM 的进展中起着至关重要的作用。我们还发现绿原酸对体外和体内高血糖诱导的病理改变均有效。
