Abstract
The incidence of cardiac dysfunction after myocardial infarction (MI) continues to increase despite advances in treatment. Excessive myocardial fibrosis plays a vital role in the development of adverse cardiac remodeling and deterioration of cardiac function. Understanding the molecular and cellular mechanism of the fibrosis process and developing effective therapeutics are of great importance. Salvia miltiorrhiza and Carthamus tinctorius extract (SCE) is indicated for angina pectoris and other ischemic cardiovascular diseases in China. SCE has been shown to inhibit the platelet activation and aggregation, ameliorate ROS-induced myocardial necrosis by inhibiting mitochondrial permeability transition pore opening, and promote angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF). However, whether SCE has effect on cardiac fibrosis after MI is not fully clear. Here, a mouse model of MI was established to observe the effect of SCE upon survival, cardiac function, myocardial fibrosis, and inflammation. Quantitative PCR and western blot assays were used to determine the expression of genes related to transforming growth factor-β (TGF-β) cascade and inflammatory responses in vivo. Additionally, the effects of SCE upon the collagen production, TGF-β/Smad3 (SMAD family member 3) signaling, and the levels of histone methylation in primary cardiac fibroblasts were detected. We found that SCE treatment significantly improved survival and left ventricular function in mice after MI. Inhibition of inflammation and fibrosis, as well as decreased expression of Smad3, was observed with SCE treatment. In TGF-β-stimulated cardiac fibroblasts, SCE significantly decreased the expression of collagen, α-smooth muscle actin (α-SMA), and Smad3. Furthermore, SCE treatment downregulated the levels of H3K4 trimethylation (H3K4me3) and H3K36 trimethylation (H3K36me3) at the Smad3 promoter region of cardiac fibroblasts, leading to inhibition of Smad3 transcription. Our findings suggested that SCE prevents myocardial fibrosis and adverse remodeling after MI with a novel mechanism of suppressing histone methylation of the Smad3 promoter and its transcription.
Highlights
Heart failure following acute myocardial infarction remains a leading cause of global morbidity and mortality [1]
Our findings suggested that Salvia miltiorrhiza and Carthamus tinctorius extract (SCE) prevents myocardial fibrosis and adverse remodeling after myocardial infarction (MI) with a novel mechanism of suppressing histone methylation of the Smad3 promoter and its transcription
We found that attenuation of SCE on fibrosis was associated with downregulation of transforming growth factor-β (TGF-β)/Smad3 signaling and SCE reduced increased levels of H3K4me3 and H3k36me3 in the Smad3 promoter region induced by TGF-β in cardiac fibroblasts (CFs)
Summary
Heart failure following acute myocardial infarction remains a leading cause of global morbidity and mortality [1]. With the advances in reperfusion therapy, guidelinerecommended medications, and devices for ventricular unloading, in-hospital mortality has decreased substantially to less than 5% [2]. Due to the combination of reduced short-term mortality and insufficient long-term treatment to survivors after MI, the incidence of heart failure is gradually increasing [3, 4]. Myocardial fibrosis, characterized as deposition of collagen and accumulation of cardiac fibroblasts (CFs), is the pathological hallmark in left ventricular (LV) remodeling. The contribution of fibrosis to infarcted hearts varies depending on specific phases and sites after abrupt total occlusion of a coronary artery. Reparative fibrosis in the infarcted area triggered by myocardial loss is critical for wound
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