Abstract 5660: Essential Role of Non-muscle Myosin Light Chain Kinase in Hypoxia-induced Murine Pulmonary Hypertension
Introduction: The pulmonary arterial hypertension (PAH) phenotype shares several pathways involved in cancer pathobiology. We previously demonstrated that the multi-kinase inhibitor, sorafenib, ameliorates rodent PAH (Moreno-Vinasco et al 2008) with genomic signatures which strongly implicated the endothelial cell cytoskeleton in the development of PAH vascular remodeling including non-muscle caldesmon, Rho-kinase and both smooth muscle- and non-muscle myosin light chain kinase (nmMLCK) isoforms. We hypothesized that the acto-myosin machinery present within lung endothelium are critical to the development of PAH in a murine model of hypoxia-induced pulmonary hypertension.
Methods: Wild type (WT) and genetically engineered mice with targeted deletion of the nmMLCK allele were exposed to normoxia, or to hypoxia and SU5416, a VEGFR-1,2 inhibitor that induces severe PH (3.5 weeks). WT and nmMLCK KO mice were assessed for hemodynamics and histopathology.
Results: Hypoxia-SU5416 WT mice developed pulmonary artery phenotype with significant increases in diphosphorylated MLC levels (2-fold, no change in total MLC), increased mean right ventricular systolic pressures (RVSP) and hypertrophy (RV/LV+S) and increased hematocrit when compared to WT-normoxic controls. However, in response to hypoxia/SU, nmMLCK-KO mice displayed reduced pMLC, significant decreases in right ventricular hypertrophy (27.3% decrease), in RVSP (25% decrease) without changes in hematocrit. Histopathology indicates reduced peri-vascular infiltration and remodeling in the nmMLCK KO mice compared to WT controls.
Conclusions: Our results are consistent with the notion that myosin light chains (MLC) are a canonical and downstream mediator of mechanical events underlying the actin-myosin interactions in lung endothelium during PH remodeling and nmMLCK is a potential therapeutic target in PAH-mediated remodeling.