Salvia miltiorrhiza and Carthamus tinctorius Extract Prevents Cardiac Fibrosis and Dysfunction after Myocardial Infarction by Epigenetically Inhibiting Smad3 Expression.
Jing YangBo WangNa LiQingqing ZhouWenhui ZhouZhenzhen ZhanPublished in: Evidence-based complementary and alternative medicine : eCAM (2019)
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.
Keyphrases
- transforming growth factor
- left ventricular
- epithelial mesenchymal transition
- poor prognosis
- oxidative stress
- vascular endothelial growth factor
- dna methylation
- mouse model
- hypertrophic cardiomyopathy
- signaling pathway
- transcription factor
- heart failure
- acute myocardial infarction
- endothelial cells
- gene expression
- left atrial
- combination therapy
- coronary artery disease
- long non coding rna
- cardiac resynchronization therapy
- dna damage
- emergency department
- metabolic syndrome
- type diabetes
- acute coronary syndrome
- atrial fibrillation
- high resolution
- mitral valve
- body mass index
- drug induced
- transcatheter aortic valve replacement
- skeletal muscle
- binding protein
- single molecule
- blood brain barrier
- liver fibrosis
- coronary artery
- physical activity
- adverse drug
- weight gain
- percutaneous coronary intervention
- high glucose