Abstract
Background: Cardiac fibrosis after myocardial infarction mainly causes cardiac diastolic and systolic dysfunction, which results in fatal arrhythmias or even sudden death. Id2, a transcriptional repressor, has been shown to play an important role in the development of fibrosis in various organs, but its effects on cardiac fibrosis remain unclear. This study aimed to explore the effects of Id2 on cardiac fibrosis after myocardial infarction and its possible mechanisms.Methods: This study was performed in four experimental groups: control group, treatment group (including TGF-β1, hypoxia or MI), treatment+GFP group and treatment+Id2 group. In vitro anoxic and fibrotic models were established by subjecting CFs or NRVMs to a three-gas incubator or TGF-β1, respectively. An animal myocardial infarction model was established by ligating of the left anterior descending coronary artery followed by directly injecting of Id2 adenovirus into the myocardial infarct’s marginal zone.Results: The results showed that Id2 significantly improved cardiac EF and attenuated cardiac hypertrophy. The mRNA and protein levels of α-SMA, Collagen I, Collagen III, MMP2 and TIMP1 were higher in treatment+Id2 group than those in treatment group as well as in treatment+GFP group both in vivo and in vitro. Immunofluorescence revealed that both α-SMA and vimentin were co-expressed in the treatment group and GFP group, but the co-expression were not detected in the control group and Id2 group. Additionally, our findings illustrated that Id2 had protective effects demonstrated by its ability to inhibit the TGF-β1/Smad3/HIF-1α/IL-11 signaling pathways. Besides, over-expression of Id2 reduced cardiomyocytes apoptosis.Conclusion: In conclusion, this study demonstrated that over-expression of Id2 preserved cardiac function and ameliorated adverse cardiac remodeling, which might be a promising treatment target for cardiac fibrosis and apoptosis.
Highlights
Fibrosis is defined as the accumulation of fibrillar extracellular matrix (ECM) components in a tissue or an organ
Our study aims to discover the role of Id2 group (Id2) in cardiac fibrosis and reveal it possible mechanisms
Western blot analysis affirmed that Id2 protein expression increased after 24 h and 2 weeks myocardial infarction (MI) at the border zone (Figures 1E, F)
Summary
Fibrosis is defined as the accumulation of fibrillar extracellular matrix (ECM) components in a tissue or an organ. The initial phase is followed by the proliferative phase In this phase, myofibroblasts generate excessive ECM and endothelial cells form new blood vessels. In the subsequent remodeling phase, activated myofibroblasts (derived from local fibroblasts) stimulate wound contraction. This process confers protection by maintaining the left ventricular structure after infarction. Myofibroblasts activation and excessive ECM accumulation lead to permanent cardiac fibrosis, which is often accompanied with cardiac systolic insufficiency, arrhythmia and adverse cardiovascular events (Jun and Lau, 2018). The two main approaches used to inhibit cardiac fibrosis after MI are as follows: preventing the cause such as alleviating endogenous EMT; slowing the rate of progression i.e., the rate at which cardiac fibroblasts are transformed into myofibroblasts cells and the rate at which ECM is stacked. This study aimed to explore the effects of Id2 on cardiac fibrosis after myocardial infarction and its possible mechanisms
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