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We focus on understanding the mechanism and signal transduction pathway underlying cardiac dysfunction that arises from myocardial infarction and cardiac hypertrophy, apparent risk factors for heart failure. Specifically, our interests center around the role of the mechanistic target of rapamycin (mTOR), which is intimately related to the insulin/phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway. In order to investigate the role of mTOR in the heart, we utilize a variety of in vitro, in vivo, and ex vivo models. Recombinant DNA is employed in both cells via the use of gene transfer and animals via the generation of transgenic mice. We are studying mice engineered with cardiac-specific overexpression of mTOR in order to see if changes in disease processes related to heart failure occur. While mTOR inhibitor rapamycin is known to prevent cardiac hypertrophy induced by pathological stresses such as pressure-overload, the role of cardiac mTOR on cardiac function under the models of cardiac diseases has not been fully defined. My laboratory reported that mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Recently our study using the transgenic mice has demonstrated that overexpression of cardiac mTOR is sufficient to protect the heart against ischemia-reperfusion injury in both in vivo and ex vivo models. These findings strongly suggest that the mTOR signaling pathway plays an important role in cardioprotection under multiple stresses such as myocardial infarction.
The second major target in my laboratory is heart failure in diabetic mellitus. Diabetes is an independent risk factor for both heart failure and ischemic heart disease. After myocardial infarction, heart failure develops at twice the rate in diabetic patients as in nondiabetic patients. Type 2 (non-insulin-dependent) diabetes occurs more commonly than type 1 (insulin-dependent) diabetes and comprises more than 90% of all case of diabetes. In addition, rising rates of obesity and physical inactivity are increasing the prevalence of type 2 diabetes, especially in Hawaii. These considerations have led us to focus on type 2 diabetes in order to find efficient therapies to reduce mortality of cardiac disease in diabetes. As mentioned above, since mTOR is one of important molecules in insulin signaling pathway, my laboratory focuses on determining the role of mTOR in diabetic hearts and exploring the mTOR signaling pathway with the idea that it may present a novel therapeutic target for treatment of heart failure in diabetes.
In order to investigate the role of mTOR in the heart, my laboratory utilizes a variety of in vitro, in vivo, and ex vivo models of heart failure with genetically manipulated models of mTOR such as transgenic and knockout mice. Hopefully, an enhanced comprehension of the mechanism underlying cardiac dysfunction will lead to the identification of novel therapeutic targets along the mTOR signal transduction pathway for the treatment of heart failure.
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Matsui, Takashi