Jun-ichi Abe, M.D., Ph.D.

Abe Lab Page

Jun-ichi Abe, M.D, Ph.D. Associate Professor Jun-ichi_Abe@urmc.rochester.edu Primary Appointment: Department of Medicine in the Aab Cardiovascular Research Institute GEBS Cluster Affiliation: CVS-Cardivascular Sciences Aab Cardiovascular Research Institute of the University of Rochester School of Medicine and Dentistry 211 Bailey Road Rm. A210D West Henrietta, NY 14586 Phone: (585) 276-9794 Fax (585) 276-9830

Dr. Abe received his M.D. from the University of Yamagata, Japan in 1987. He was a senior medical fellow as well as an Instructor in Cardiology/Medicine in The First Department of Medicine at the University of Tokyo, Japan from 1991 to 1994. He received his Ph.D. Cardiology/Medicine from University Tokyo in 1998. Before arriving at the University of Rochester Medical Center in 1999, Dr. Abe was an Acting Instructor in Department of Medicine, Cardiology Division at the University of Washington. His basic research was done in Yoh Takuwa's laboratory at the University of Tokyo, and Bradford C. Berk's laboratory at University of Washington where he characterized several growth factors and molecules in vascular remodeling. His major research interests include the biology of PPAR in endothelial inflammation, and oxidative stress-mediated signaling in ischemic heart.

Research Overview

The research in Dr. Abe's lab focus on the mechanism of atherosclerosis and myocardial infarction, especially in the role of oxidative stress, hypoxia, and hyperglycemia. Actually, it has been reported that 466,101 deaths by myocardial infarction in the United States in 1997 (one of every 5 deaths). Additionally, 1,100,000 new and recurrent cases suffer from heart attack per year, and over 40 % die. Oxidative stress, hypoxia, and hyperglycemia play an important role in heart damage after myocardial infarction. The treatment of myocardial infarction involves the re-opening of the coronary artery (thrombolysis or angioplasty). The response to these treatments is significant, but in many cases it is hard to avoid cardiac dysfunction, even if the procedure is successful. The prognosis of patients who suffer from severe heart failure after myocardial infarction is generally significantly poor. In addition, with over ten million patients diagnosed and another five million undiagnosed, diabetes mellitus and its complications, including cardiovascular disease has become a major public health problem.

The mechanism responsible for oxidative stress, hypoxia, and hyperglycemia-mediated cardiovascular injury remains unknown. The major goal of Dr. Abe's lab is to understand the molecular mechanisms of atherosclerosis formation and heart failure, and also determine the mechanism of diabetes, which significantly increases the risk of cardiac mortality. They have focused on oxidative stress, hypoxia, and hyperglycemia action via the mitogen-activated protein kinase (MAP) family in atherosclerosis and cardiac dysfunction, and have tried to clarify the mechanisms responsible for oxidative, hyperglycemia, and hypoxic injury. Currently, they are investigating the role of p90RSK and ERK5 kinases in heart damage and atherosclerosis by using genetically manipulated animals (transgenic mice). Their goal is to detect the pathyphysiological meaning of these molecules in the process of atherosclerosis and heart failure, and move forward to develop more effective treatment of heart disease and to improve the prognosis of those affected by ischemic and diabetic heart disease as described in the following:

1. The mechanism of diabetic cardiomyopathy
   There is increasing support for the idea that excessive production of reactive oxygen species (ROS) contributes to the pathogenesis of diabetes. They have developed a novel hypothesis based on data from our laboratory that p90 ribosomal S6 kinase (p90RSK) is a physiological substrate of PKC (beta) 2, and that Troponin I (TnI) phosphorylation by p90RSK contributes to decreased cardiac function in diabetes. Dr. Abe and his colleagues have generated cardiac-specific p90RSK and dominant negative p90RSK transgenic mice and determined the role of p90RSK in diabetic cardiomyopathy.
2. Role of ERK5/PPARg in atherosclerosis formation
   Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands inhibit adhesion molecule expression in activated endothelial cells and significantly reduce monocyte/macrophage homing to atherosclerotic plaques. They have found that steady laminar flow activates ERK5, and increases PPAR gamma transcriptional activation. In addition, hinge-helix1 region of PPAR gamma fragment specifically disrupts ERK5/PPAR gamma interaction and inhibits activated ERK5-mediated PPAR gamma activation, supporting the specific role of ERK5 and PPAR gamma interaction in laminar flow-mediated anti-inflammatory effect. Based on their exciting preliminary data, they hypothesize that laminar flow acts as an anti-inflammatory modulator by increasing PPAR gamma transcriptional activity, and decreasing VCAM-1 expression in endothelial cell. They will determine endothelial ERK5, JNK, NF-kappa B, and VCAM-1 expression in atherosclerosis model in mice by using en face confocal microscopy, and we will use endothelial specific constitutively active form (CA) of MEK5 alpha or ERK5 knock out in LDLR-/- knock out (KO) mice, which has been characterized by atherosclerosis formation. They anticipate that pioglitazone and/or CA-MEK5 alpha inhibits and ERK5 KO will promote atherosclerosis formation.

Recent Publications

1. Takeishi Y Abe J*, Lee JD, Walsh, RA Berk BC. Differential Regulation of p90RSK and BMK1 by Ischemia/Reperfusion and Oxidative Stress in Perfused Guinea Pig Hearts. Circ Res. 1999. 85: 1164-1172.
   *Corresponding author
2. Abe J, Okuda M, Huang Q, Yoshizumi M, Berk BC. Reactive Oxygen Species Activate p90 Ribosomal S6 Kinase via Fyn and Ras. J Biol Chem. 2000 Jan. 21;275(3):1739-1748.
3. Abe J, Yoshizumi M, Haendeler J, Huang Q, Berk BC. Src and Cas mediate JNK activation but not ERK1/2 and p38 kinases by Reactive Oxygen Species. J Biol Chem. 2000. 275:11706-11712.
4. Abe J*, Takeishi Y*, Huang Q*, Che W, Lee J-D, Kawakatsu H, Hoit B.D., Berk B.C., Walsh R.D. Src and multiple MAP kinase activation in cardiac hypertrophy and in congestive heart failure under chronic pressure-overload: Comparison with acute pressure-overload model in guinea pig heart. Journal of Mol Cell Cardio. 2001. 33:1637-1648.
5. Takeishi Y*, Huang Q*, Yoshizumi M, Lee JD, Kawakatsu H, Baines CP, Che W, Walsh RA, Berk BC, Abe J*. Src family kinase and adenosine differentially regulate multiple MAP kinases in ischemic myocardium: Modulation by Ischemic Preconditioning. J Mol Cell Cardiol. 2001. 33(11):1989-2005.
6. Abe J*, Takeishi Y*, Huang Q*, Che W, Lee J-D, Kawakatsu H, Hoit B.D., Berk B.C., Walsh R.D. Activation of Multiple Mitogen-Activated Protein Kinases and p90 Ribosomal S6 Kinase in Failing Human Hearts with dilated cardiomyopathy. Cardiovasc Res. 2002. 53(1):131-7.
7. Che W*, Lerner-Marmarosh N*, Huang Q, Osawa M, Ohta S, Yoshizumi M, Glassman M, Lee JD, Yan C, Berk BC, and Abe J*#. Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: Role of Gab1 and MEKK3 in TNF- alpha induced c-Jun and NF- kappa B activation and adhesion molecule expression. Circ Res. 2002. Jun 14;90(11):1222-30
8. Huang Q*, Lerner-Marmarosh N*, Che W, Ohta S, Osawa M, Yoshizumi M, Glassman M, Yan C, Berk BC, and Abe J*#. The novel role of C-terminal region of SHP-2: Involvement of Gab1 and SHP-2 phosphatase activity in Elk-1 activation. J. Biol. Chem. 2002. 277: 29330-29341
9. Abe J*, Cameron SJ*, Malik S, Akaike M, Lerner-marmarosh N, Yan C, Lee JD, Yang J. Regulation of Epidermal Growth Factor-induced Connexin 43 Gap Junction Communication by Big Mitogen-Activated Kinase 1/ERK5 but not ERK1/2 Kinase Activation. J. Biol. Chem. 2003. 278:18682-8
10. Lerner-Marmarosh N, Yoshizumi M, Che W, Surapisitchat J, Kawakatsu H, Akaike M, Ding B, Huang Q, Yan C, Berk BC, Abe J. Inhibition of Tumor Necrosis Factor-a-Induced SHP-2 Phosphatase Activity by Shear Stress. A Mechanism to Reduce Endothelial Inflammation. Arterioscler Thromb Vasc Biol. 2003 Oct. 23(10):1775-1781.
11. Abe J*, Cameron SJ*, Malik S, Che W, Yang J. Differential role of MEK5 alpha and MEK5 beta in BMK1/ERK5 activation. J Biol Chem. 2004. 279:1506-1512
12. Osawa M, Itoh S, Ohta S, Huang Q, Berk BC, Marmarosh NL, Che W, Ding B, Yan C, and Abe J. ERK1/2 associates with the c-Met binding domain of Gab1: Role in ERK1/2 and Egr-1 nuclear accumulation. J Biol Chem. 2004. 79(28):29691-9
13. Cameron SJ, Itoh S, Baines CP, Zhang C, Ohta S, Che W, Glassman M, Lee JD, Yan C, Yang J, and Abe J. Activation of Big MAP Kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion. FEBS letter. 2004 May. 21;566(1-3):255-60
14. Akaike M, Che W, Lerner-Marmarosh N, Ohta S, Osawa M, Ding B, Berk BC, Yan C, and Abe J. Hinge-helix1 region of PPAR gamma1 mediates interaction with ERK5 and PPAR gamma1 transcriptional activation: Involvement in flow-induced PPAR gamma activation in endothelial cells. Mol Cell Biol., Oct. 24(19):8691-8704
15. Abe J*, Ding B*, Wei H, Huang Q, Walsh RA, Molina CA, Zhao A, Sadoshima J, Blaxall BC, Berk BC, Yan C. Functional role of phosphodiesterase 3A (PDE3A) in cardiomyocyte apoptosis: Implication in heart failure. Circulation. 2005 May 17;111(19):2469-76 .
16. Itoh S, Ding B, Bains C.P., Wang N, Takeishi Y, Jalili T, King GL, Walsh RA, Yan C, and Abe J. Role of p90 Ribosomal S6 Kinase (p90RSK) in reactive oxygen species and PKCb-mediated cardiac Troponin I phosphorylation. J Biol Chem. 2005 Jun 24;280(25):24135-42.
17. Itoh S, Lemay S, Osawa M, Che W, Duan Y, Tompkins A, Brookes PS, Sheu SS, and Abe J. Mitochondrial Dok-4 recruits Src kinase and regulates NF-kB activation in endothelial cells. J Biol Chem. 2005 Jul 15;280(28):26383-96.
18. Abe J*, Ding B, Wei H, Xu H, Che W, Aizawa T, Liu W, Molina CA, Sadoshima J, Blaxall BC, Berk BC, Yan C. A positive feedback loop pf phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Proc Natl Acad Sci USA, 2005 Oct 11;102 (41):14771-6. (Editorial 102: 14483-14484)
19. Itoh S, Ding B, Shishido T, Lerner-Marmarosh N, Wang N, Maekawa N, Berk BC, Takeishi Y, Yan C, Blaxall BC, and Abe J. Role of p90 Ribosomal S6 Kinase (p90RSK)-mediated Pro-renin Converting Enzyme (PRECE) in Ischemic and Diabetic Myocardium. Circulation, 2006 Apr 11;113(14):1787-1798.
20. Abe J*, Maekawa N*, Shishido T, Ding B, Itoh S, Sharma VK, Sheu SS, Blaxall BC, Berk BC. Inhibiting p90 ribosomal S6 kinase prevents cardiac ischemia-reperfusion injury. Circulation, 2006; 113:2516-2523.
21. Woo C-H, Massett MP, Shishido T, Itoh S, Ding B, McClain C, Che W, Vulapalli SR, Yan C, Abe J. ERK5 activation inhibits inflammatory responses via peroxisome proliferators-activated receptor delta (PPARdelta ) stimulation. J Biol Chem. 2006 Oct 27;281(43):32164-74.
22. Yan C, Ding B, Shishido T, Woo C-H, Itoh S, Jeon K-I, Liu W, Xu H, McClain C, Molina CA, Blaxall BC, Abe J. Activation of ERK5 reduces cardiac apoptosis and dysfunction via inhibition of a PDE3A-ICER feedback loop. Circ Res. 2007 Mar 2;100(4):510-9.
23. Garin G, Abe J, Mohan A, Lu W, Yan C, Newby AC, Rhaman A, Berk BC. Flow Antagonizes TNF-{alpha} Signaling in Endothelial Cells by Inhibiting Caspase-Dependent PKC{zeta} Processing. Circ Res. 2007 Jul 6;101(1):97-105
24. Woo C-H, Shishido T, McClain C, Lim JH, Li JD, Yang J, Yan C, Abe J. ERK5-SUMOylation antagonizes shear stress-induced anti-inflammatory response and eNOS expression in endothelial cells. Circ Res. 2007 in press

* Equally contributed 1st author