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Role of microtubules in myocyte contractile dysfunction during cardiac hypertrophy in the rat
Y Ishibashi1, H Tsutsui, S Yamamoto
1Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Abstract:
We have shown that increased microtubules cause myocyte contractile dysfunction in feline right ventricular pressure-overload hypertrophy. To investigate the association between the progression of cardiac hypertrophy and microtubules and to delineate the role of microtubules in contractile defects in hypertrophied myocytes, we assessed the amounts of free and polymerized tubulin proteins, using Western blot analysis and immunofluorescence micrograph, and evaluated the sarcomere mechanics of myocytes isolated from rats with pressure-overload left ventricular (LV) hypertrophy. Total and polymerized tubulins were progressively and persistently increased in LV after the imposition of pressure overload. The increase in microtubules was associated with the development and progression of hypertrophy and not the immediate response to the stress loading to the myocardium. The contractile function of hypertrophied myocytes was depressed in parallel with the increase in microtubules. Depolymerization of microtubules normalized the initially depressed LV myocyte contractile function. Thus the progressive increase of microtubule density during LV hypertrophy due to persistent pressure overloading to the myocardium may cause the consequent myocyte contractile dysfunction.
Insights
Increased microtubules contribute to heart muscle cell dysfunction during left ventricular hypertrophy. Depolymerizing these microtubules restored normal heart cell function in pressure-overloaded rats.
Area of Science:
- Cardiovascular Biology
- Cellular Physiology
- Cardiac Remodeling
Background:
- Cardiac hypertrophy, particularly left ventricular (LV) hypertrophy, is often associated with impaired myocyte contractile function.
- The role of cytoskeletal dynamics, specifically microtubules, in the progression of cardiac dysfunction during hypertrophy remains incompletely understood.
Purpose of the Study:
- To investigate the association between the progression of cardiac hypertrophy and microtubule dynamics.
- To determine the role of microtubules in contractile defects within hypertrophied myocytes.
Main Methods:
- Utilized Western blot analysis and immunofluorescence microscopy to quantify free and polymerized tubulin in rat hearts.
- Isolated myocytes from rats subjected to pressure-overload-induced left ventricular hypertrophy.
- Evaluated sarcomere mechanics to assess myocyte contractile function.
Main Results:
- Progressive and persistent increases in total and polymerized tubulin were observed in the LV following pressure overload.
- The rise in microtubule density correlated with the development and progression of cardiac hypertrophy.
- Contractile function of hypertrophied myocytes was depressed in parallel with increased microtubule density.
- Depolymerization of microtubules led to the normalization of depressed LV myocyte contractile function.
Conclusions:
- The progressive increase in microtubule density during left ventricular hypertrophy, induced by sustained pressure overload, is a key factor contributing to myocyte contractile dysfunction.
- Microtubule dynamics represent a potential therapeutic target for mitigating contractile deficits in cardiac hypertrophy.