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Role of microtubules in contractile dysfunction of hypertrophied cardiocytes
H Tsutsui1, H Tagawa, R L Kent
1Department of Medicine, Medical University of South Carolina, Charleston.
Insights
Pressure overload causes cardiac hypertrophy and contractile dysfunction by increasing microtubules, which impede sarcomere motion. This finding may explain the progression from hypertrophy to heart failure.
Area of Science:
- Cardiovascular Biology
- Cellular Physiology
- Biomedical Research
Background:
- Cardiac hypertrophy from pressure overload often leads to contractile dysfunction.
- The underlying cause of this dysfunction has remained unclear.
- Volume overload-induced hypertrophy does not typically result in contractile dysfunction, suggesting a mechanism beyond mere cellular enlargement.
Purpose of the Study:
- To investigate if increased stress, rather than strain, in pressure-overloaded cardiac cells causes dysfunction.
- To test the hypothesis that excess microtubules impede sarcomere motion in hypertrophied cardiomyocytes.
- To identify the role of the cytoskeleton in pressure-induced cardiac contractile dysfunction.
Main Methods:
- Feline right ventricles were pressure overloaded (pulmonary artery banding) or volume overloaded (atrial septotomy).
- Microtubule quantity was assessed using immunoblots and immunofluorescent microscopy.
- Sarcomere motion was measured during microtubule depolymerization to evaluate mechanical effects.
Main Results:
- Stress loading significantly increased the microtubule component of the cardiac muscle cell cytoskeleton.
- This increase in microtubules was responsible for the observed contractile dysfunction in pressure-hypertrophied myocardium.
- No similar effects were observed in volume-overloaded or normal hearts, or in left ventricular cells.
Conclusions:
- Excess microtubules in cardiomyocytes are a direct cause of contractile dysfunction in pressure-overloaded cardiac hypertrophy.
- These microtubule-induced abnormalities are persistent and may contribute to the progression to congestive heart failure.
- Targeting microtubule dynamics could be a therapeutic strategy for heart failure resulting from pressure overload.
Abstract:
Cardiac hypertrophy in response to systolic pressure overloading frequently results in contractile dysfunction, the cause for which has been unknown. Since, in contrast, the same degree and duration of hypertrophy in response to systolic volume overloading does not result in contractile dysfunction, we postulated that the contractile dysfunction of pressure hypertrophied myocardium might result from a direct effect of stress as opposed to strain loading on an intracellular structure of the hypertrophied cardiocyte. The specific hypothesis tested here is that the microtubule component of the cytoskeleton is such an intracellular structure, which, forming in excess, impedes sarcomere motion. The feline right ventricle was either pressure overloaded by pulmonary artery banding or volume overloaded by atrial septotomy. The quantity of microtubules was estimated from immunoblots and immunofluorescent micrographs, and their mechanical effects were assessed by measuring sarcomere motion during microtubule depolymerization. We show here that stress loading increases the microtubule component of the cardiac muscle cell cytoskeleton; this apparently is responsible for the entirety of the cellular contractile dysfunction seen in our model of pressure-hypertrophied myocardium. No such effects were seen in right ventricular cardiocytes from normal or volume-overloaded cats or in left ventricular cardiocytes from any group of cats. Importantly, the linked microtubule and contractile abnormalities are persistent and thus may be found to have significance for the deterioration of initially compensatory cardiac hypertrophy into the congestive heart failure state.