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. Metzger, Stephen L. Archer

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 (US)
Article numbere006195
JournalJournal of the American Heart Association
Volume6
Issue number6
DOIs
StatePublished - Jun 1 2017

Bibliographical note

Funding Information:
Prins is funded by NIH F32 HL129554. Tian and Wu are funded by Canadian Vascular Network Scholar Awards. Thenappan is funded by American Heart Association Scientist Development Grant 15SDG25560048. Metzger is funded by NIH RO1s HL122323 and HL132874. Archer is supported by Canada Foundation for Innovation (229252 and 33012), NIH RO1s HL113003 and HL071115, a Tier 1 Canada Research Chair in Mitochondrial Dynamics and Translational Medicine (950-229252), and a grant from the William J. Henderson Foundation.

Keywords

  • Pulmonary hypertension
  • Right ventricular failure
  • Right ventricular pressure overload
  • T-tubules

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