Matsui Laboratory researchers are investigating major issues related to heart failure following myocardial infarction and cardiac hypertrophy.
1. Heart Failure Caused by Myocardial Infarction and Cardiac Hypertrophy
Heart failure is a leading cause of hospitalization and mortality. We are examining changes in signal transduction pathways caused by myocardial infarction and cardiac hypertrophy, two important precipitants of heart failure. Specifically, we explore 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. We have examined the effects of cardiac-specific overexpression of mTOR on disease processes related to heart failure. While the mTOR inhibitor rapamycin can prevent cardiac hypertrophy induced by pathological stress, the role of cardiac mTOR in ventricular function has not been defined. We reported that cardiac mTOR prevents cardiac dysfunction in pathological hypertrophy and ischemia-reperfusion injury (ref. 1, 3 and 4). We continue to look for potential therapeutic approaches for patients with heart failure caused by cardiac hypertrophy or myocardial infarction.
Ex vivo Langendorff perfused heart system
In vitro gene transfer in adult cardiomyocytes
2. Heart Failure in Diabetes
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 non-diabetic patients. Rising rates of obesity and physical inactivity are leading to increased prevalence of type 2 diabetes, and this is especially evident in Hawaii. These considerations have encouraged us to search for therapies to reduce cardiac-related mortality in diabetes. Because of the important role of mTOR in insulin signaling, we are working to determine the role of mTOR in diabetic hearts, and exploring the mTOR signaling pathway as a novel therapeutic target for treatment of heart failure in diabetes (ref. 1).
In vivo model of ischemia-reperfusion injury (ref. 2)
1. Aoyagi T, Higa JK, Aoyagi H, Yorichika N, Shimada BK, Matsui T. Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2015;308(12):H1530-1539.
2. Katz MY, Kusakari Y, Aoyagi H, Higa JK, Xiao C-Y, Abdelkarim AZ, Marh K, Aoyagi A, Rosenzweig A, Lozanoff S, Matsui T. Three dimensional myocardial scarring along myofibers after coronary ischemia-reperfusion revealed by computerized images of histological assays. Physiol Rep. 2014;2 (7): e12072 (open-access article), doi: 10.14814/phy2.12072.
3. Aoyagi T, Kusakari Y, Xiao C-Y, Inouye BT, Takahashi M, Scherrer-Crosbie M, Rosenzweig A, Hara K, Matsui T. Cardiac mTOR protects the heart against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2012;303(1):H75-85.
4. Song X, Kusakari Y, Xiao C-Y, Kinsella SD, Rosenberg MA, Scherrer-Crosbie M, Hara K, Rosenzweig A, Matsui T. mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Am J Physiol Cell Physiol. 2010;299(6):C1256-66
Dr. Takashi Matsui
Department of Anatomy, Biochemistry & Physiology