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Role of microtubules in the contractile dysfunction of hypertrophied myocardium
1Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, Veterans Administration Medical Center, Charleston 29425-5799, USA. zilem@musc.edu
Insights
Microtubule depolymerization using colchicine normalized cardiac tissue contractility in cats with pressure overload hypertrophy. This suggests microtubule density is key to both cellular and tissue-level contractile dysfunction.
Area of Science:
- Cardiovascular Physiology
- Cell Biology
- Cardiac Hypertrophy Research
Background:
- Increased microtubule density impairs cardiocyte function in pressure overload cardiac hypertrophy.
- Colchicine-induced microtubule depolymerization restores contractility in isolated hypertrophied cardiocytes.
- The effect of microtubule depolymerization on cardiac tissue function in hypertrophy remained unclear.
Purpose of the Study:
- To investigate if microtubule depolymerization benefits cardiac tissue function in pressure overload hypertrophy.
- To assess the role of microtubule density in myocardial contractile dysfunction.
Main Methods:
- Isolated right ventricular (RV) papillary muscles from cats with 4-week pulmonary artery banding (PAB)-induced hypertrophy and controls.
- Measurement of contractile function before and after colchicine treatment (10(-5) mol/liter).
- Assessment of microtubule density via indirect immunofluorescence confocal microscopy.
Main Results:
- PAB significantly increased RV pressure and weight; decreased developed tension, shortening extent, and shortening rate.
- PAB muscles showed increased microtubule density.
- Colchicine normalized contractility in PAB papillary muscles without affecting controls.
Conclusions:
- Excess microtubule density contributes significantly to myocardial contractile dysfunction in chronic pressure-overload cardiac hypertrophy.
- Microtubule depolymerization is a potential therapeutic target for cardiac dysfunction in hypertrophy.
Objectives:
We sought to determine whether the ameliorative effects of microtubule depolymerization on cellular contractile dysfunction in pressure overload cardiac hypertrophy apply at the tissue level.
Background:
A selective and persistent increase in microtubule density causes decreased contractile function of cardiocytes from cats with hypertrophy produced by chronic right ventricular (RV) pressure overloading. Microtubule depolymerization by colchicine normalizes contractility in these isolated cardiocytes. However, whether these changes in cellular function might contribute to changes in function at the more highly integrated and complex cardiac tissue level was unknown.
Methods:
Accordingly, RV papillary muscles were isolated from 25 cats with RV pressure overload hypertrophy induced by pulmonary artery banding (PAB) for 4 weeks and 25 control cats. Contractile state was measured using physiologically sequenced contractions before and 90 min after treatment with 10(-5) mol/liter colchicine.
Results:
The PAB significantly increased RV systolic pressure and the RV weight/body weight ratio in PAB; it significantly decreased developed tension from 59+/-3 mN/mm2 in control to 25+/-4 mN/mm2 in PAB, shortening extent from 0.21+/-0.01 muscle lengths (ML) in control to 0.12+/-0.01 ML in PAB, and shortening rate from 1.12+/-0.07 ML/s in control to 0.55+/-0.03 ML/s in PAB. Indirect immunofluorescence confocal microscopy showed that PAB muscles had a selective increase in microtubule density and that colchicine caused complete microtubule depolymerization in both control and PAB papillary muscles. Microtubule depolymerization normalized myocardial contractility in papillary muscles of PAB cats but did not alter contractility in control muscles.
Conclusions:
Excess microtubule density, therefore, is equally important to both cellular and to myocardial contractile dysfunction caused by chronic, severe pressure-overload cardiac hypertrophy.