SIRT3 inhibits Ang II-induced transdifferentiation of cardiac fibroblasts through β-catenin/PPAR-γ signaling.

AIMS: Cardiac fibrosis is an inevitable process of numerous cardiovascular diseases in which the transdifferentiation of cardiac fibroblasts plays a pivotal role. Sirtuin3 (SIRT3) has been believed to protect against cardiac fibrosis. However, the mechanism underlying this beneficial effect has not yet been elucidated. In this study, we investigated the potential mechanism of SIRT3 on the inhibition of fibroblast-to-myoblast transdifferentiation.

MAIN METHODS: Cells were stimulated by angiotension II (Ang II) with SIRT3 overexpression or knockdown. Also, PPARγ agonist (Pioglitazone PIO) and inhibitor (GW9662) were used to confirm the antifibrotic effect of PPARγ. Western blot, qRT-PCR, CCK-8 and immunofluorescence staining analysis were used for investigation.

KEY FINDINGS: Our data demonstrated that overexpression of SIRT3 prevented the transdifferentiation of CFs while SIRT3 knockdown promoted the process. Simultaneously, SIRT3 overexpression increased total PPARγ expression and suppressed the acetylated PPARγ. Besides, pretreatment with PPARγ agonist, pioglitazone protected CFs from transdifferentiation while PPARγ inhibitor prevented the protective effect of SIRT3. In addition, we have found that SIRT3 upregulated the expression of PPARγ by degeration of β-catenin.

SIGNIFICANCE: Our findings indicate that this newly identified SIRT3/β-catenin/PPAR-γ axis will provide novel insight into the understanding of the mechanism of transdifferentiation of CFs to myofibroblasts.