Takashi Matsui, M.D., Ph.D.
Deputy Director, Professor & Chair
Department of Anatomy, Biochemistry & Physiology
Center for Cardiovascular Research
John A. Burns School of Medicine
651 Ilalo Street, BSB 222
Honolulu, HI 96813
Phone: (808) 692-1554
The Matsui Lab is focused on the insulin signaling pathway in cardiomyocytes, especially cardioprotective effects against pathological settings such as ischemia. Specifically, our interests center around the role of the mechanistic target of rapamycin (mTOR), which is intimately related to the insulin 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.
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. We reported that cardiac mTOR prevents cardiac dysfunction in pathological hypertrophy and ischemia-reperfusion injury. Recently the Matsui lab demonstrated that mTOR is necessary and sufficient for cardiomyocyte protection against iron-mediated cell death that includes excessive iron-induced cell death and ferroptosis that is an iron-dependent form of regulated cell death. This is the first report that ferroptosis is a significant type of cell death in cardiomyocytes. We are currently defining the pathophysiological role of ferroptosis in cardiac diseases such as acute myocardial infarction and heart failure.
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.
Shimada BK, Yorichika N, Higa JK, Baba Y, Kobayashi M, Aoyagi T, Suhara T, Matsui T. mTOR-mediated calcium transients affect cardiac function in ex vivo ischemia-reperfusion injury. Physiol Rep. 2021;9:e14807. doi: 10.14814/phy2.14807
Yorichika N, Baba Y, Shimada BK, Thakore M, Wong SM, Kobayashi M, Higa JK, Matsui T. The effects of Tel2 on cardiomyocyte survival. Life Sci. 2019 Sep 1;232:116665. doi: 10.1016/j.lfs.2019.116665.
Kobayashi M, Suhara T, Baba Y, Kawasaki KK, Higa JK, Matsui T. Pathological roles of iron in cardiovascular disease. Curr Drug Targets. 2018;19(9):1068-1076. doi: 10.2174/1389450119666180605112235.
Baba Y, Higa JK, Shimada BK, Horiuchi KM, Suhara T, Kobayashi M, Woo JD, Aoyagi H, Marh KS, Kitaoka H, Matsui T. Protective effects of the mechanistic target of rapamycin against excess iron and ferroptosis in cardiomyocytes. Am J Physiol Heart Circ Physiol. 2018;314:H659-H668 (selected in Editor Picked Articles and posted on Podcast. The Best Paper Award 2019, Research Article)
Suhara T, Baba Y, Shimada BK, Higa JK, Matsui T. The mTOR signaling pathway in myocardial dysfunction in type 2 diabetes mellitus. Curr Diab Rep. 2017;17(6):38.
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.
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.
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.
Aoyagi T,Matsui T . Phosphoinositide-3 kinase signaling in cardiac hypertrophy and heart failure. Current Pharmaceutical Design 2011;17:1818-1824
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 2010;299(9):C1255-66. (see Editorial Focus in the issue, 2010;299(9):C1250-52)