TMZ improved cardiac function, alleviated myocardial injury and oxidative stress, and reduced the myocardial infarct area and apoptosis. TMZ inhibited MI/R-induced myocardial autophagy, H/R-induced H9c2 cell apoptosis, and autophagy flux. The effect of TMZ on autophagy was repressed by LY294002. TMZ protected against MI/R injury by inhibiting excessive autophagy via activating the AKT/mTOR pathway.

Tissue nonspecific alkaline phosphatase (TNAP) is expressed widely in different tissues, modulating functions of metabolism and inflammation. However, the effect of TNAP on cardiac fibrosis remains controversial and needs to be further studied. The present study aims to investigate the role of TNAP on myocardial infarction (MI)-induced fibrosis and its mechanism. TNAP was upregulated in patients with MI, both in serum and injured hearts, and predicted inhospital mortality. TNAP was also significantly upregulated after MI in rats, mostly in the border zone of the infarcted hearts combined with collagen synthesis. Administration of TNAP inhibitor, tetramisole, markedly improved cardiac function and fibrosis after MI. In the primary cultures of neonatal rat cardiac fibroblasts (CFs), TNAP inhibition significantly attenuated migration, differentiation, and expression of collagen-related genes. The TGF-β1/Smads signaling suppression, and p-AMPK and p53 upregulation were involved in the process. When p53 inhibitor was administered, the antifibrotic effect of TNAP inhibition can be blocked. This study provides a direct evidence that inhibition of TNAP might be a novel regulator in cardiac fibrosis and exert an antifibrotic effect mainly through AMPK-TGF-β1/Smads and p53 signals.

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