Activated Interstitial Myofibroblasts Express Catabolic Enzymes and Mediate Matrix Remodeling in Myxomatous Heart Valves

Abstract

Background-The mechanisms of extracellular matrix changes accompanying myxomatous valvular degeneration are uncertain. Methods and Results-To test the hypothesis that valvular interstitial cells mediate extracellular matrix degradation in myxomatous degeneration by excessive secretion of catabolic enzymes, we examined the functional characteristics of valvular interstitial cells in 14 mitral valves removed for myxomatous degeneration from patients with mitral regurgitation and in 11 normal mitral valves obtained at autopsy. Immunohistochemical staining assessed (1) cell phenotype using antibodies to ␣-actin (microfilaments), vimentin and desmin (intermediate filaments), smooth muscle myosin (SM1), and SMemb (a nonmuscle myosin produced by activated mesenchymal cells) and (2) the expression of proteolytic activity using antibodies to collagenases (matrix metalloproteinase [MMP]-1, MMP-13), gelatinases (MMP-2, MMP-9), cysteine endoproteases (cathepsin S and K), and interleukin-1␤, a cytokine that can induce secretion of proteolytic enzymes. Although interstitial cells in normal valves stained positively for vimentin, but not ␣-actin or desmin, cells in myxomatous valves contained both vimentin and ␣-actin or desmin (characteristics of myofibroblasts). Moreover, cells in myxomatous valves strongly expressed SMemb, MMPs, cathepsins, and interleukin-1␤, which were weakly stained in controls. Nevertheless, interstitial cells in both groups strongly expressed procollagen-I mRNA (in situ hybridization), suggesting preserved ability to synthesize collagen in myxomatous valves. Conclusions-Interstitial cells in myxomatous valves have features of activated myofibroblasts and express excessive levels of catabolic enzymes, without altered levels of interstitial collagen mRNA. We conclude that valvular interstitial cells regulate matrix degradation and remodeling in myxomatous mitral valve degeneration.

Development of a Simultaneous Cryo-Anchoring and Radiofrequency Ablation Catheter for Percutaneous Treatment of Mitral Valve Prolapse

“…3). 37 These tissue level changes cause MV leaflets with myxomatous disease to become thickened and enlarged, and the redundant tissue of these leaflets leads to poor leaflet coaptation and MR. 37 Morphologic analysis of myxomatous MVs has shown a greater than two-fold increase in valve surface area, due to significant increases in both the anterior and posterior leaflet surface areas. 25 Additionally, the structural elements of the MVcollagen, elastin, and proteoglycans -constitute approximately 85-95% of leaflet dry weight, 7,28 indicating that alteration of these components will significantly affect leaflet mechanical properties.…”

“…The etiology is unknown at this time. 37 The current gold standard to correct MVP is open-chest surgical valve repair or replacement, which is highly undesirable for elderly patients. In the past decade, percutaneous treatment of MV disease has received a great deal of interest.…”

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

“…12,17 Overexpression of TGF-␤ is often observed in in vivo wound sites. 12 It is also present in several heart valverelated diseases (eg, calcific aortic stenosis, 18,19 mitral valve prolapse, 20,21 and Marfan syndrome). 22 By using a well-characterized wound model, 11 we also reported an up-regulation of TGF-␤ at the in vitro wound edge.…”

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

“…Notch2 is highly expressed in AVC (E12. 5) and OFT (E11.5 and E14.5) endocardium and cushion mesenchyme and is expressed in atrial and ventricular myocardium at later time points [145,146]. Notch3 is expressed in the cardiac crescent only during its formation [143] whereas Notch4 is expressed in E10.5 endocardium during cushion formation [147].…”