Recent studies have demonstrated that CAS is an active, regulated disease process akin to atherosclerosis, in which resident cells undergo remodeling and transformation. Normal valves harbor a low percentage of smooth muscle cells (SMCs) however their role in CAS is not defined. We analyzed 12 normal and 22 calcified valves for early and late differentiated SMC markers by immunocytochemistry. Expression of myocardin and myocardin-related transcription factors (MRTFA/B) was analyzed. TGFβ1 was used to activate MRTFs in valve interstitial cells and transmission electron microscopy (TEM) was used to detect the presence of SMCs in areas of calcification. The expression of SMC markers calponin, SM1, SM2 and SM22 was increased in all 22 calcified valves with caldesmon, SMC myosin, SMC α-actin and desmin increased in 40-91% of calcified valves. SMC markers were abundantly and aberrantly expressed in surface and microvessel endothelial cells and vasculature in 40% of the calcified valves. Normal valves showed expression of myocardin, MRTF-A and -B in the base of the ventricularis, similar to the pattern of SMC in normal valves. An aberrant expression of myocardin, MRTF-A and MRTF-B, was found in 71%, 53% and 67%, respectively, of calcified valves, in a similar pattern to the aberrant expression of SMC markers. In calcified valves the expression of MRTFs was nuclear in both valve interstitial cells and endothelial cells suggestive of activation. Nuclear expression of MRTF-A was increased by 11-fold in VICs treated with TGFβ1 (10ng/ml) (p<0.05). TEM of the fibrosa layer of calcified valves showed bundles of SMCs and SMC-derived foam cells. In conclusion, SMCs are are aberrantly expressed around calcified nodules and in endothelial cells in CAS with myocardin and MRTFs, key regulators of SMC expression, abundantly expressed. These findings strongly suggest that the SMC phenotype plays an important role in the pathophysiology of CAS.


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