Aortic valve disease is estimated to affect 2% of the United States population. the increased expression of transcription factors in diseased AoV that are common to valvulogenic and osteogenic processes. These studies lend support to the idea that a developmental gene program is re-activated in aortic valve disease and may contribute to the molecular mechanisms underlying valve calcification in disease. downstream of RANKL signaling (30-32). Expression of specific components of the stratified ECM is dependent on transcription factors that are also active in cartilage tendon and bone development (10). Sox9 is required for cartilage lineage development and also is expressed in the remodeling valves. Targeted loss of Sox9 in mouse heart valve development prevents valve maturation and leads to A-966492 decreased expression of Col2 and cartilage link protein which are characteristic of proteoglycan-rich ECM related to cartilage (14). Scleraxis a bHLH transcription factor first identified in developing tendons also is expressed in the remodeling valves with the tendinous matrix markers tenascin and collagen 14 (33 34 Overall there is increasing evidence that each of these transcription factors controls the expression of genes related to specific ECM characteristics of the mature stratified valves. Furthermore as discussed later many of these transcription factors are re-activated during aortic valve disease and may play a role in an osteogenic-like process during valve calcification. Transcription factors and aortic valve pathogenesis Features of valve sclerosis include disorganization of collagen bundles loss of valve cusp stratification and increased activity of A-966492 ECM remodeling enzymes (35 36 (Figure 2-C). AoV disease is a narrowing of the valve opening which often includes calcification of the valve cusps Rabbit polyclonal to ACTR5. (Figure 2-D) (3). Valve calcification occurs primarily in the fibrosa layer in regions of greatest mechanical stress and calcium deposits often protrude on the aortic surface of the valve (37). Two patterns of calcification have A-966492 been described. The first beginning at the valve hinge where the cusp attaches to the aortic wall and the second initiating along the line of coaptation the point at which the AoV cusps meet during diastole (38). Histologically the majority of valve calcification is thought to be dystrophic (passive) however cartilaginous nodules and mature lamellar bone have also been described suggesting an active calcification process has been underappreciated (39). Figure 2 The progression of AoV disease The valvular interstitial cells (VIC) are the main cellular constituents of the mature valves and contribute to valve homeostasis as well as valve pathogenesis. The VIC in a healthy valve arise from valve progenitor cells of the developing endocardial cushions are primarily quiescent and are important for maintaining normal valve structure and function (Figure 2-A) (40). Conversely in a diseased valve the VIC become activated to a myofibroblast state and express the marker alpha smooth muscle actin (Figure 2-B) (20 40 Other cell populations including infiltrating immune cells and resident valve stem cells have also been described in diseased AoV (39 41 Quiescent VIC do not proliferate whereas activated VIC have been shown to undergo cell proliferation A-966492 (42). There is accumulating evidence that the activated proliferating VIC initiate a transcriptional program common to heart valve progenitors and osteogenic processes. Recent studies report the expression of transcription factors associated with valve and bone formation in human diseased AoV. In limb morphogenesis Msx2 is important for the proliferation of osteogenic progenitor cells A-966492 and for bone and cartilage formation through the regulation of the canonical Wnt signaling pathway (15 43 Likewise in human diseased AoV Msx2 expression is increased in calcified areas associated with increased Wnt signaling and cell proliferation (21 42 Similarly Twist1 is expressed in the osteoblast progenitors where it inhibits osteoblast differention while promoting chondrogenesis (12). In human diseased AoV Twist1.