BPS2026 – Targeting the regulation and function of Cnn2 to alleviate pathogenic fibrosis and calcification

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder, especially affecting the aging population. Current clinical management is limited to surgical valve replacement to correct hemodynamic dysfunction. However, recent data have shown that the progression of heart failure continues after valve replacement, pressing for the development of a pharmacological prevention. Myofibroblastic and calcific differentiations of aortic valve interstitial cells (AVIC) drive the pathogenesis and progression of CAVD. Biomechanical signaling plays a major role in AVIC differentiation into myofibroblasts and osteogenic-like cells. Calponin 2, encoded by Cnn2 gene, is an actin cytoskeleton-associated regulatory protein functioning in smooth muscle contraction and non-muscle cell motility under mechanoregulations (PMID: 38515654). Previous work in our lab found that Cnn2 deletion attenuates aortic valve calcification in ApoE −/− mice, indicating calponin 2’s role in cellular mechanosensing during the pathogenesis and progression of CAVD (PMID: 30053524). To further investigate the function of calponin 2 in fibrotic and calcific tissue remodeling, the present study aims to unravel the mechanistic basis of Cnn2 mechanoregulation in myofibroblast differentiation and calcification. Using immortalized mouse embryonic fibroblasts (MEFs) derived from wild-type and Cnn2 knockout mice cultured on gel substrates of low vs. high stiffness, TGF-β1-induced myofibroblast differentiation and calcification are studied. The results have shown that the sensitivity to TGF-β1 induction is higher in wild-type MEFs than that of Cnn2 knockout cells as measured by the expression of myofibroblast markers. Cnn2 expression and calcific differentiation both depend on the stiffness of culture substrate. Studies on the effect of calponin 2 regulation on extracellular matrix mechanical property and TGF-β1 bioavailability are underway to advance our understanding of the pathogenesis of CAVD with the ultimate goal of developing a new therapeutic target for non-surgical treatment and prevention.