They express hematopoietic markers and produce ECM. drive fibrosis in cardiovascular pathologies, and it is crucial to understand the impact and contribution of the various mechanisms for A66 the control of fibrosis before the onset of a severe pathological consequence. gene . Although the Smad independent signaling activated by TGF- that includes extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and phosphatidylinositol 3-kinase (PI3K) Mouse monoclonal to PR has not been investigated in AVS so far, it is possible that TGF-1 exerts its fibrotic function through a multitude of effector molecules. In atherosclerosis, TFG- has been associated with both atherogenic and atheroprotective properties. Experimental studies related to atherogenic properties of TGF- reported that TGF- induced proteoglycan production in SMCs, as well as stabilized the atherosclerotic lesions. Additionally, inhibition of TFG- signaling by anti-TGF- A66 antibodies reduced collagen content in the lesions, leading to exacerbation of atherosclerotic lesions . Contrary to the reported atherogenic role, clinical data from as early as two decades ago has indicated a negative correlation between serum TGF-1 levels and advanced atherosclerosis , and these findings have also been supported by recent experimental studies in mice models reporting an atheroprotective role of TGF- [29,30]. TGF- also regulates expression of 8 integrins in the neointima, which is required for contractile properties and communication with the extracellular matrix . As TGF- is a pleiotropic cytokine produced by multiple cell types, its impact on fibrosis is highly complex and context-dependent. Individual studies in any single-cell population are not sufficient to delineate the complex function of TGF-. Complete inhibition of TFG- activity is possibly not a viable option for controlling fibrosis in AVS due to its pleiotropic effects. However, inhibitors of the TGF- receptor, which may decrease TGF- activity, could be potentially beneficial. 4.2. Renin-Angiotensin System Synthesis of Ang II and activation of the renin-angiotensin system is a key feature in aortic valve stenosis. Ang II is generated from angiotensin I by the action of angiotensin-converting enzyme A66 (ACE) [5,32]. AT1, a receptor for Ang II, is expressed only in fibroblasts of sclerotic lesions , where their activation by Ang II mediates fibroblast proliferation, ECM production, cholesterol accumulation in macrophages, and increased oxidative stress [5,33]. ACE has been shown to co-localize in the sclerotic lesion with LDL and Ang II, and in resident macrophages in the lesions, where it stimulates the generation of ROS and promotes the LDL-induced pathogenesis of AVS . Ang II negatively regulates the expression of MMP1 and enhances collagen accumulation in cardiac fibroblasts . Unlike fibroblasts in sclerotic lesions, SMCs consistently express AT1, and Ang II has been known to trigger their proliferation and migration to the outer layer of the plaque, contributing to a negative remodeling of the vessel walls [36,37]. The concerted action of ROS and Ang II stimulates the differentiation of adventitial fibroblasts into myofibroblasts through the p38 MAPK and JNK pathway . Ang II is also known to increase TGF-1 expression in cardiac hypertrophy , as A66 TGF- also regulates p38 MAPK signaling; therefore, it may be possible that Ang II and TGF- function cooperatively, as shown in the study by Schultz et al., which demonstrated TGF-1 as an important mediator for Ang II-induced cardiac hypertrophy . Although contradictory reports exist regarding the efficacy of ACE inhibitors in aortic stenosis [41,42], it may be possible to target the angiotensin pathway, particularly AT1 inhibition, to control fibrosis, and to at least partially inhibit the undesirable effects of TGF- overexpression in the fibrosis of AVS. 4.3. Immune Cells and Cytokines Expression of the pro-inflammatory cytokines, TGF-, tumor necrosis factor (TNF), IL-1, and IL-6 is consistently observed in atherosclerosis and AVS. Under the influence of inflammatory cytokines, fibroblasts themselves produce multiple cytokines and are responsive to many more, which induce their differentiation into myofibroblasts, as well as regulate the ECM organization. In the heart valves, fibroblasts have been shown to secrete TGF-1 and activate TGF–Smad A66 signaling upon.