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Takashi Matsui MD, PhD
Affiliation:
University of Hawaii
Anatomy, Biochemistry & Physiology
"Cardiovascular and Related Diseases"
Title: Professor and Associate Chair
Rank: Professor
Address:
651 Ilalo ST BSB 110
Honolulu, HI 96813
Contact:
Email: [email protected]
Telephone: 808-692-1554
Narrative
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.
Awards and Honors
1997 1999 American Heart Association, - American Heart Association Fellowship Award
1997
Pfizer Pharmaceutical Grant for Research on Coronary Artery Disease, - The Japan
Heart Foundation Investigator Award
1999
Massachusetts General Hospital, - Calderwood Prize, Division of Cardiac Surgery
2000 2005 NIH, NHLBI, - Mentored Clinical Scientist Development Award (K08)
2000
Heart Failure Society of America, - The Young Investigator Award
2001
American Heart Association, - Trainee Abstract award at the Annual Scientific Session
2012
American Journal of Physiology Heart and Circulatory Physiology, - 2011 Star
Reviewer
Publications
1.
Aoyagi T, Higa JK, Aoyagi H, Yorichika N, Shimada BK, Matsui T. Cardiac mTOR PubMed
rescues the detrimental effects of diet-induced obesity in the heart after ischemiareperfusion. Am J Physiol Heart Circ Physiol. 2015 Jun 15; 308(12):H1530-9.
2.
Katz MY, Kusakari Y, Aoyagi H, Higa JK, Xiao CY, Abdelkarim AZ, Marh K, Aoyagi T, PubMed
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).
3.
Dai J, Matsui T, Abel ED, Dedhar S, Gerszten RE, Seidman CE, Seidman JG, PubMed
Rosenzweig A. Deep Sequence Analysis of Gene Expression Identifies Osteopontin as
a Downstream Effector of Integrin-Linked Kinase (ILK) in Cardiac-Specific ILK
Knockout Mice. Circ Heart Fail. 2014 Jan 1; 7(1):184-93.
4.
Aoyagi T, Kusakari Y, Xiao CY, Inouye BT, Takahashi M, Scherrer-Crosbie M, PubMed
Rosenzweig A, Hara K, Matsui T. Cardiac mTOR protects the heart against ischemiareperfusion injury. Am J Physiol Heart Circ Physiol. 2012 Jul; 303(1):H75-85.
5.
Aoyagi T, Matsui T. Phosphoinositide-3 kinase signaling in cardiac hypertrophy and PubMed
heart failure. Curr Pharm Des. 2011; 17(18):1818-24.
6.
Song X, Kusakari Y, Xiao CY, Kinsella SD, Rosenberg MA, Scherrer-Crosbie M, Hara K, PubMed
Rosenzweig A, Matsui T. mTOR attenuates the inflammatory response in
cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Am J
Physiol Cell Physiol. 2010 Dec; 299(6):C1256-66.
7.
Kusakari Y, Xiao CY, Himes N, Kinsella SD, Takahashi M, Rosenzweig A, Matsui T.
Myocyte injury along myofibers in left ventricular remodeling after myocardial
infarction. Interact Cardiovasc Thorac Surg. 2009 Dec; 9(6):951-5.
PubMed
8.
Morissette MR, Cook SA, Foo S, McKoy G, Ashida N, Novikov M, Scherrer-Crosbie M, PubMed
Li L, Matsui T, Brooks G, Rosenzweig A. Myostatin regulates cardiomyocyte growth
through modulation of Akt signaling. Circ Res. 2006 Jul 7; 99(1):15-24.
9.
Matsui T, Nagoshi T, Hong EG, Luptak I, Hartil K, Li L, Gorovits N, Charron MJ, Kim PubMed
JK, Tian R, Rosenzweig A. Effects of chronic Akt activation on glucose uptake in the
heart. Am J Physiol Endocrinol Metab. 2006 May; 290(5):E789-97.
10. Nagoshi T, Matsui T, Aoyama T, Leri A, Anversa P, Li L, Ogawa W, del Monte F, PubMed
Gwathmey JK, Grazette L, Hemmings BA, Hemmings B, Kass DA, Champion HC,
Rosenzweig A. PI3K rescues the detrimental effects of chronic Akt activation in the
heart during ischemia/reperfusion injury. J Clin Invest. 2005 Aug; 115(8):2128-38.
11. Aoyama T, Matsui T, Novikov M, Park J, Hemmings B, Rosenzweig A. Serum and PubMed
glucocorticoid-responsive kinase-1 regulates cardiomyocyte
hypertrophic response. Circulation. 2005 Apr 5; 111(13):1652-9.
survival
and
12. Matsui T, Rosenzweig A. Convergent signal transduction pathways controlling PubMed
cardiomyocyte survival and function: the role of PI 3-kinase and Akt. J Mol Cell
Cardiol. 2005 Jan; 38(1):63-71.
13. Matsui T, Nagoshi T, Rosenzweig A. Akt and PI 3-kinase signaling in cardiomyocyte PubMed
hypertrophy and survival. Cell Cycle. 2003 May-Jun; 2(3):220-3.
14. Chao W, Matsui T, Novikov MS, Tao J, Li L, Liu H, Ahn Y, Rosenzweig A. Strategic PubMed
advantages of insulin-like growth factor-I expression for cardioprotection. J Gene
Med. 2003 Apr; 5(4):277-86.
15. Cook SA, Matsui T, Li L, Rosenzweig A. Transcriptional effects of chronic Akt PubMed
activation in the heart. J Biol Chem. 2002 Jun 21; 277(25):22528-33.
16. Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, Liao R, Rosenzweig A. PubMed
Phenotypic spectrum caused by transgenic overexpression of activated Akt in the
heart. J Biol Chem. 2002 Jun 21; 277(25):22896-901.
17. Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, PubMed
Rosenzweig A. Akt activation preserves cardiac function and prevents injury after
transient cardiac ischemia in vivo. Circulation. 2001 Jul 17; 104(3):330-5.
18. Gerszten RE, Friedrich EB, Matsui T, Hung RR, Li L, Force T, Rosenzweig A. Role of PubMed
phosphoinositide 3-kinase in monocyte recruitment under flow conditions. J Biol
Chem. 2001 Jul 20; 276(29):26846-51.
19. Matsui T, Li L. Adenoviral gene transfer of activated phosphatidylinositol 3'-kinase PubMed
and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation. 1999 Dec
7; 100(23):2373-9.
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