Secretory products from epicardial adipose tissue induce adverse myocardial remodeling after myocardial infarction by promoting reactive oxygen species accumulation

Abstract

Adverse myocardial remodeling, manifesting pathologically as myocardial hypertrophy and fibrosis, often follows myocardial infarction (MI) and results in cardiac dysfunction. In this study, an obvious epicardial adipose tissue (EAT) was observed in the rat model of MI and the EAT weights were positively correlated with cardiomyocyte size and myocardial fibrosis areas in the MI 2- and 4-week groups. Then, rat cardiomyocyte cell line H9C2 and primary rat cardiac fibroblasts were cultured in conditioned media generated from EAT of rats in the MI 4-week group (EAT-CM). Functionally, EAT-CM enlarged the cell surface area of H9C2 cells and reinforced cardiac fibroblast activation into myofibroblasts by elevating intracellular reactive oxygen species (ROS) levels. Mechanistically, miR-134-5p was upregulated by EAT-CM in both H9C2 cells and primary rat cardiac fibroblasts. miR-134-5p knockdown promoted histone H3K14 acetylation of manganese superoxide dismutase and catalase by upregulating lysine acetyltransferase 7 expression, thereby decreasing ROS level. An in vivo study showed that miR-134-5p knockdown limited adverse myocardial remodeling in the rat model of MI, manifesting as alleviation of cardiomyocyte hypertrophy and fibrosis. In general, our study clarified a new pathological mechanism involving an EAT/miRNA axis that explains the adverse myocardial remodeling occurring after MI.

Importance of cardiac imaging assessment of epicardial adipose tissue after a first episode of myocardial infarction

“…Quantification of EAT and its relation with cardiovascular disease has been described in several publications (2)(3)(4)(5); in our study, the best cut-off value to predict outcome was 4 mm. Previous studies have linked EAT to CAD; Ahn et al (10) described that epicardial fat thickness values > 3.0 mm were independently associated with the presence of CAD.…”

“…This EAT is found between the myocardium and the visceral pericardium and it can directly regulate myocardial response after a MI; without the presence of a muscle fascia, there is the possibility that crosstalk between the EAT and the myocardium occurs, causing an increase in the levels of secretory products -chemokines and cytokines- from EAT. This has a potential association with myocardial fibrosis development, with the functional consequences it might have ( 2 , 3 ). The pathogenesis of CAD includes multiple mechanisms, such as inflammation, oxidative damage, endothelial dysfunction, lipidic accumulation, and glucotoxicity; EAT seems to have a role in all of these processes ( 4 ).…”

Qiliqiangxin Modulates the Gut Microbiota and NLRP3 Inflammasome to Protect Against Ventricular Remodeling in Heart Failure

“…As previously mentioned, cardiac remodeling, caused or exacerbated by varying pathological changes, will eventually result in serious consequences, for which there are no effective drugs ( Hao et al, 2021 ; Ni et al, 2022 ; Ren et al, 2021 ). New therapeutic strategies are needed to be introduced clinically for protecting against pressure overload-induced cardiac injury ( Li X. et al, 2021 ) or targeting adverse post-MI left ventricle remodeling ( Germano et al, 2020 ).…”

“…As one of the most prevalent cardiac dysfunctions, heart failure (HF) is caused by multiple cardiac diseases like coronary heart disease, hypertension, arrhythmia, and viral myocarditis ( Zhong et al, 2021 ), characterized by high morbidity and mortality ( Ren et al, 2021 ; Sokolski et al, 2022 ). A significant pathological basis of HF is cardiac remodeling, which is thought to play a key part in the clinical outcomes of heart diseases ( Liu et al, 2021 ) and occurs through various complex mechanisms, leading to changes such as pathological cardiac hypertrophy, interstitial fibrosis, increased degradation of the myocardial extracellular matrix, impaired heart functions, and even HF ( Hao et al, 2021 ; Ni et al, 2022 ; Ren et al, 2021 ). Cardiac remodeling in HF is typically characterized by myocardial hypertrophy ( Zhong et al, 2021 ), which is initially an adaptive and compensatory response to maintain the ejection fraction under increased pressure load, while irreversible damage could be induced if pathological overload persists, along with inflammatory responses, vascular dysfunction, increased extracellular matrix deposition, myocardial fibrosis, and all pathologic changes resulting in cardiac dysfunction ( Nemska et al, 2021 ; Tsuda, 2021 ; Zhong et al, 2021 ).…”

Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis

“…In addition, p300/CBP-associated factor (PCAF), a histone acetyltransferase, is also elucidated to be required for the activation of CFs in response to TGF-β1 [ 59 ]. Intriguingly, miR-134-5p knockdown protected myocardial remodeling and cardiac fibrosis in the rat model of MI by upregulating lysine acetyltransferase 7 expression and histone H3K14 acetylation [ 77 ].…”