Pulmonary arterial hypertension (PAH) is a rare but lethal cardiovascular disorder characterized by pulmonary vascular remodeling leading to right ventricular (RV) dysfunction. Currently, PAH therapies primarily target the pulmonary vasculature despite the fact that RV function is the major determinant of clinical outcomes. Here, we investigated the hypothesis that colchicine, a microtubule depolymerizing agent, improves RV function by increasing junctophilin-2 by targeting a pathologically remodeled microtubule cytoskeleton.
Methods and results
Western blot, confocal microscopy, tissue analysis, echocardiography, cardiac catheterization, and treadmill exercise were used to examine how colchicine altered phenotypic severity of the monocrotaline (MCT) PAH rat model. One week after MCT injection, rats were treated with phosphate buffered saline or colchicine for 3 weeks. In the RV of MCT rats, there was increased microtubule density, reduced junctophilin-2 protein levels with loss of t-tubule localization pattern, and t-tubule disarray. Colchicine increased junctophilin-2 levels and improved localization patterns, and partially corrected t-tubule morphology. Also, colchicine reduced RV hypertrophy and improved RV function. Colchicine also regressed pulmonary vascular disease, evident by a lower mean pulmonary arterial pressure, lower total pulmonary vascular resistance, and increased pulmonary artery (PA) acceleration time. Colchicine enhanced RV-PA coupling suggesting that the observed improvement in RV function was not solely due to regression of pulmonary vascular disease. Finally, colchicine-treated rats had increased exercise capacity and improved survival.
Colchicine increases junctophilin-2 expression and normalizes t-tubule architecture of RV cardiomyocytes in MCT rats leading to improved RV function and RV-PA coupling.