The SIRT3 deacetylase blocks cardiac fibrosis by targeting TGFβ1‐Smad3 signaling (1152.6)

Cardiac fibrosis after myocardial injury is a major challenge in the medicine today to preserve heart function. At the cellular level, activation of TGFβ1 signaling is considered a major contributor of cardiac fibrosis. However, the underlying mechanism of TGFβ activation is not yet completely understood. SIRT3 is a mitochondrial deacetylase which is activated by exercise and calorie restriction. SIRT3 regulates variety of mitochondrial functions, including metabolism, ROS synthesis and apoptosis. SIRT3KO mice spontaneously develop cardiac fibrosis with age. This study was undertaken to test the hypothesis whether SIRT3 deficiency leads to transformation of cardiac fibroblasts (CF) into myofibroblasts (myoFB) and excessive synthesis of extracellular matrix (ECM). CF obtained from adult rat hearts were subjected to SIRT3 knockdown (KD) by using siRNA. Differentiation of CF to myoFB was determined by increased expression of myoFB markers, like smooth muscle α‐actin, fibronectin and collagen1. The results showed robust expression of myoFB markers in SIRT3KD cells. To test whether SIRT3 deficiency contributed to this phenotype, we re‐expressed SIRT3 and found that this intervention changed back myoFB phenotype of SIRT3‐deficient cells to normal CF. Similar results were obtained when TGFβ1‐induced myoFB were over expressed with SIRT3, thus demonstrating the ability of SIRT3 to block transformation of CF into myoFB and synthesis of excessive ECM. Mechanistic studies showed increased levels of TGFβ1 and Smad3 in SIRT3KD cells, which were resistant to use of the anti‐oxidant, N‐acetyl cysteine. These data thus demonstrated an anti‐fibrotic role of SIRT3, which is independent of its ability to regulate cellular oxidative stress. Grant Funding Source : NIH‐NHLBI