Regulation of Nexilin by transcription factors affected by actin dynamics in smooth muscle cells

Nexilin (NEXN) is an actin filament-binding protein that is located in Z-skeletal and skeletal muscle cells. These anchor the actin filaments to the plasma membrane and are necessary for normal muscle contraction. NEXN mutations cause destabilization of Z discs and lead to cardiomyopathy. We have preliminary data showing tight correlations between NEXN and smooth muscle transcriptional regulators (YAP1 and myocardial-related transcription factors (MRTF). Both of these transcriptional activators communicate changes in the actin cytoskeleton to the genome and are important for regulating smooth muscle cell differentiation. In this research proposal we want to test the hypothesis that MRTF and YAP contribute to NEXN transcription and that this is regulated via actin dynamics, that is, the degree of actin polymerization. This will be studied by depolymerizing / polymerizing the actin cytoskeleton as well as over / under expressing YAP1 and MRTF. The promoter of Nexilin will be studied and mutated to understand which gene sequences are important for the expression of Nexilin. Furthermore, we want to study the importance of Nexilin in smooth muscle by creating a muscle-specific NEXN knock-out mouse. In this model, we want to study how the absence of Nexilin affects the vascular function of mice and how hypertension induced by angiotensin II in these mice will affect the vascular stability and development of aneurysms. No previous studies have investigated Nexilin in smooth muscle. Proposed studies are therefore completely novel and aim at understanding NEXN's smooth muscle function on molecular, cellular and physiological levels. Increased knowledge of NEXN's effects in vascular smooth muscle may have consequences for future new therapies for the prevention of atherosclerosis and high blood pressure.