Dapagliflozin inhibits TGF-β-induced transdifferentiation of valvular interstitial cells and mitral valvular degeneration

Myxomatous mitral valve (MV) disease (MMVD) is a common cardiac condition in humans and dogs. Currently, no therapeutic agent is available for MMVD that can prevent MV degeneration. Transforming growth factor (TGF)-β-induced transdifferentiation of valvular interstitial cells (VICs) is a key process in MV degeneration. Dapagliflozin is used to treat type 2 diabetes, and it alleviates cardiac and renal fibrosis by inhibiting the TGF-β signaling pathway. In this study, we investigated the effect of dapagliflozin on TGF-β-induced transdifferentiation of VICs and MV degeneration in rats. Protein expression levels and contractile forces generated by VICs were determined using western blotting and a collagen gel contraction assay, respectively. Structural changes of the MV were detected using histological staining. Dapagliflozin inhibited TGF-β-induced Smad2/3 phosphorylation and increased alpha-smooth muscle actin expression and the cellular contractile force. In contrast, dapagliflozin increased the activity of adenosine monophosphate-activated protein kinase (AMPK)α. However, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside, an AMPK activator, inhibited TGF-β-induced Smad2/3 phosphorylation. AMPKα gene knockdown impeded the inhibitory effect exerted by dapagliflozin on TGF-β-induced Smad2 phosphorylation. Additionally, dapagliflozin increased AMPKα phosphorylation and suppressed TGF-β-induced MV degeneration, alpha-smooth muscle actin expression, and Smad2/3 phosphorylation in isolated rat MV. To the best of our knowledge, this study is the first to demonstrate that dapagliflozin inhibits TGF-β-induced VIC differentiation and subsequent MV degeneration by suppressing Smad signaling via AMPK activation, suggesting that dapagliflozin is a potential novel therapeutic agent for MMVD. KEY MESSAGES: TGF-β-induced VIC differentiation leads to MV degeneration. DAPA, an SGLT2 inhibitor, suppresses the TGF-β signaling pathway. DAPA inhibits TGF-β-induced differentiation of rat VIC via AMPK activation. DAPA inhibits TGF-β-induced degeneration and signal transduction in isolated rat MV. DAPA suppresses MV degeneration by inhibiting VIC differentiation.