Colchicine Depolymerizes Microtubules, Increases Junctophilin-2, and Improves Right Ventricular Function in...

Area of Science:

• Cardiology
• Pulmonary Medicine
• Pharmacology

Background:

• Pulmonary arterial hypertension (PAH) is a severe condition with significant right ventricular (RV) dysfunction.
• Mechanisms underlying RV dysfunction in PAH are not well understood, and targeted therapies are limited.
• Abnormal microtubular structure and reduced junctophilin-2 (JPH2) expression in RV cardiomyocytes are hypothesized to impair RV function in PAH.

Purpose of the Study:

• To investigate the effects of colchicine, a microtubule-depolymerizing agent, on RV function and pulmonary vascular remodeling in a rat model of monocrotaline-induced PAH.
• To determine if colchicine can restore JPH2 expression and improve RV cardiomyocyte structure.

Main Methods:

• Rats with monocrotaline-induced PAH were treated with colchicine or saline.
• Pulmonary hemodynamics, RV function, and exercise capacity were assessed using echocardiography, cardiac catheterization, and treadmill testing.
• RV cardiomyocyte microtubule density, JPH2 expression, and t-tubule morphology were examined.

Main Results:

• Monocrotaline-induced PAH led to increased RV microtubule density, reduced JPH2 expression, and t-tubule disarray.
• Colchicine treatment decreased microtubule density, increased JPH2 expression, and improved t-tubule morphology in RV cardiomyocytes.
• Colchicine therapy improved RV function, reduced RV hypertrophy, enhanced RV-pulmonary artery coupling, improved pulmonary hemodynamics, and increased exercise capacity.

Conclusions:

• Monocrotaline-induced PAH causes RV-specific microtubule derangement involving JPH2 reduction and t-tubule disarray.
• Colchicine effectively improved RV structure and function by modulating microtubule density and JPH2 expression.
• Colchicine also mitigated pulmonary vascular remodeling, supporting its potential as an RV-directed therapy for PAH.