Deletion of calponin 2 attenuates the development of calcific aortic valve disease in ApoE-/- mice.

Calcific aortic valve disease (CAVD) is a leading cause of cardiovascular mortality and lacks non-surgical treatment. The pathogenesis of CAVD involves perturbation of valvular cells by mechanical stimuli, including shear stress, pressure load and leaflet stretch, of which the molecular mechanism requires further elucidation. We recently demonstrated that knockout (KO) of Cnn2 gene that encodes calponin isoform 2, a mechanoregulated cytoskeleton protein, attenuates atherosclerosis in ApoE KO mice. Here we report that Cnn2 KO also decreased calcification of the aortic valve in ApoE KO mice, an established model of CAVD. Although myeloid cell-specific Cnn2 KO highly effectively attenuated vascular atherosclerosis that shares many pathogenic processes with CAVD, it did not reduce aortic valve calcification in ApoE KO mice. Indicating a function in the pathogenesis of CAVD, calponin 2 participates in myofibroblast differentiation that is a leading step in the development of CAVD. The aortic valves of ApoE KO mice exhibited increased expression of calponin 2 and smooth muscle actin (SMA), a hallmark of myofibroblasts. The expression of calponin 2 increased during myofibroblast-like differentiation of primary sheep aortic valve interstitial cells and during the osteogenic differentiation of mouse myofibroblasts. Cnn2 KO attenuated TGFß1-induced differentiation of myofibroblasts in culture as shown by the lower expression of SMA and less calcification than that of wild type (WT) cells. These findings present calponin 2 as a novel molecular target for the treatment and prevention of CAVD.

Diminished expression of h2-calponin in prostate cancer cells promotes cell proliferation, migration and the dependence of cell adhesion on substrate stiffness.

Calponin is an actin filament-associated protein and its h2 isoform inhibits cell motility. Here we report significant expression of h2-calponin in prostate epithelial cells, which is diminished in cancerous cells. Comparison between a prostate cancer cell line PC3 and its metastatic derivative PC3-M showed lower levels of h2-calponin in PC3-M, corresponding to faster rates of cell proliferation and migration. Substrate adhesion of PC3 and PC3-M cells was positively correlated to the level of h2-calponin and the adhesion of PC3-M exhibited a higher dependence on substrate stiffness. Such effects of h2-calponin on cell proliferation, migration and substrate adhesion were also seen in normal versus cancerous primary prostate cells. Further supporting the role of h2-calponin in inhibiting cell motility, fibroblasts isolated from h2-calponin knockout mice proliferated and migrated faster than that of wild type fibroblasts. Transfective over-expression of h2-calponin in PC3-M cells effectively inhibited cell proliferation and migration. The results suggest that the diminished expression of h2-calponin in prostate cancer cells increases cell motility, decreases substrate adhesion, and promotes adhesion on high stiffness substrates.