Tubuloside A alleviates postmyocardial infarction cardiac fibrosis by inhibiting TGM2: Involvement of inflammation and mitochondrial pathway apoptosis.

Cardiac fibrosis is associated with myocardial remodeling following myocardial infarction (MI), which can lead to heart failure, arrhythmias, and even death. This study aimed to determine the effects of tubuloside A (TA) on cardiac fibrosis after MI and elucidate their underlying molecular mechanisms. Rats were divided into the following groups: sham (fake surgery), MI, MI + 1 mg/kg TA, and MI + 3 mg/kg TA. Compared with MI, the addition of TA significantly reduced mortality, improved cardiac function, decreased infarct size, and inhibited myocardial injury and fibrosis. To verify the direct targets of TA, we used cellular thermal shift assay and drug affinity responsive target stability to analyze drug-protein interactions and discovered that TA can bind directly to TGM2 and inhibit its enzymatic activity. Furthermore, to investigate whether TA can inhibit the TGF-β1-mediated activation of cardiac fibroblasts (CFs) through TGM2, we overexpressed TGM2 in CF cells and treated them with TA. We found that TA inhibited the activity of TGM2 in CF cells and reduced α-SMA, collagen-I, and collagen-III levels, thereby inhibiting the progression of fibrosis. Similarly, we found that TA could exert anti-inflammatory and antiapoptotic effects by inhibiting TGM2. Overall, we demonstrated that TA is a potential candidate drug for inhibiting the impacts of myocardial infarction and cardiac fibrosis, reducing postinfarction fibrosis by inhibiting the NF-κB signaling pathway and suppressing mitochondrial pathway-mediated apoptosis. Therefore, focusing on drug discovery strategies for TA may provide a promising therapeutic approach for MI.