Colchicine depolymerizes microtubules, increases junctophilin-2, and improves right ventricular function in experimental pulmonary arterial hypertension

Kurt W. Prins, Lian Tian, Danchen Wu, Thenappan Thenappan, Joseph M. Metzge, Stephen L. Archer

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Abstract

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 RV‐targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin‐2 (JPH2) expression, resulting in t‐tubule derangements. Conversely, we assessed whether colchicine, a microtubule‐depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline‐induced 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 t‐tubule localization and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t‐tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV–pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity.

Conclusions
Monocrotaline‐induced PAH causes RV‐specific derangement of microtubules marked by reduction in JPH2 and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t‐tubule 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 RV‐directed therapy for PAH.
Original languageEnglish
Article numbere006195
Number of pages19
JournalJournal of the American Heart Association
Volume6
Issue number6
DOIs
Publication statusPublished - 6 Nov 2017

Keywords

  • pulmonary hypertension
  • right ventricular failure
  • right ventricular pressure overload
  • T-tubules

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    Prins, K. W., Tian, L., Wu, D., Thenappan, T., Metzge, J. M., & Archer, S. L. (2017). Colchicine depolymerizes microtubules, increases junctophilin-2, and improves right ventricular function in experimental pulmonary arterial hypertension. Journal of the American Heart Association, 6(6), [e006195]. https://doi.org/10.1161/JAHA.117.006195