Abstract 11609: Aberrant Expression of Smooth Muscle Markers and Regulators, Myocardin and MRTFA/B in Calcific Aortic Valve Disease
Similar mediators and pathogenetic pathways are invloved in calcific aortic stenosis (CAS) and atherosclerosis. Smooth muscle (SM) cells play a major role in atherosclerosis and undergo phenotypic modulation. Normal valves harbour a low percentage of smooth muscle cells however their role in CAS is not defined. We hypothesized that the SM cell phenotype plays a role in the pathophysiology of CAS. We analysed 12 normal and 22 calcified valves for early and late, differentiated SM markers by immunocytochemistry. The expression of co-activators and key regulators of SM gene expression, myocardin and myocardin-related transcription factors, (MRTFA/B), was also evaluated. Key cytokines were used to activate MRTFs and transmission electron microscopy (TEM) used to detect the presence of SM cells in atypical regions of the valve leaflets. In normal valves SM markers are localised to the base of the ventricularis. The expression of calponin, SM1, SM2 and SM22 was dysregulated (increased and in fibrosa) in all 22 calcified valves with caldesmon, SM myosin, SM α-actin and desmin dysregulated in 40-91% of calcified valves. SM markers were abundantly 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 SM 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 SM markers. The expression of MRTFs was nuclear in both valve interstitial cells (VICs) and endothelial cells in calcified valves suggestive of activation. TGFβ1 (10ng/ml) was able to upregulate the nuclear expression of MRTF-A by 11-fold in VICs (p<0.05). TEM of the fibrosa layer of calcified valves demonstrated the presence of bundles of SM cells and SM-derived foam cells. In conclusion, SM cells were abundant and SM-derived foam cells were observed in atypical regions of calcified valves. SM markers and co-activators were increased and aberrantly expressed in calcified valves. These findings strongly suggest that the SM phenotype plays an important role in the pathophysiology of CAS which has, as yet, been neglected.
- © 2012 by American Heart Association, Inc.