TGF-β1-induced calcification of valvular myofibroblasts: mechanisms and therapeutic strategies

Abstract

Aortic valve disease (AVD) is the third leading cause of cardiovascular disease and is especially prevalent among the elderly. In AVD, thickened fibrotic AV leaflets lose their ability to fully open and close, causing reduced ejection of blood out of the ventricle when the heart pumps during systole and retrograde blood flow back into the ventricle when the heart rests during diastole. Progression of AVD is characterized by stiff stenotic AV leaflets with bone-like calcific nodules. Currently, the only effective long-term treatment for AVD is replacement surgery, a high risk procedure for elderly patients. For this reason, a non-invasive therapeutic to stop the development of AVD would greatly benefit those most at risk for developing severe AVD. However, a more thorough understanding of the cellular signaling and subsequent tissue level changes involved in AVD progression is needed to elucidate relevant therapeutic targets. At the cellular level, AVD is believed to be caused by activation of AV interstitial cells (AVICs) to a myofibroblast phenotype. Once activated, AVICs increase extracellular matrix deposition, directly leading to the decreased biomechanical compliance of the leaflets observed in AVD. The pro-fibrotic cytokine transforming growth factor-β1 (TGF-β1) has been the most extensively studied initiator of AVIC myofibroblast activation, and increased levels of TGF-β1 have been observed in AV leaflets from patients with AVD. Unfortunately, due to the systemic ubiquity of its signaling, TGF-β1 is not an ideal therapeutic target for the treatment of AVD. Therefore, the overall goal of the research presented in this dissertation is to understand how both biochemical and mechanical factors alter the biological state of the AVIC with an emphasis on elucidating the molecular mechanisms that lead to pathological differentiation of AVICs. We are also interested in how these mechanisms may be targeted therapeutically to treat AVD. We will present evidence that antagonism of the serotonin 2B receptor inhibits TGF-β1-mediated pathologic differentiation of AVICs through a mechanism that involves physical arrest of non-canonical TGF-β1 signaling pathways. We believe that the outcomes of these studies may lead to novel therapeutic strategies for AVD.