1 research outputs found
Colchicine depolymerizes microtubules, increases junctophilin-2, and improves right ventricular function in experimental pulmonary arterial hypertension
Background Pulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RVâtargeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilinâ2 (JPH2) expression, resulting in tâtubule derangements. Conversely, we assessed whether colchicine, a microtubuleâdepolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotalineâinduced PAH. Methods and Results Immunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of tâtubule localization and tâtubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves tâtubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RVâpulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity. Conclusions Monocrotalineâinduced PAH causes RVâspecific derangement of microtubules marked by reduction in JPH2 and tâtubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both tâtubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RVâdirected therapy for PAH