About Dr. Abe
Dr. Jun-ichi Abe received his medical degree from the Yamagata University in 1987, and went on to pursue his Internal Medicine Residency, and continued his fellowship in cardiology at Mitsui Memorial Hospital in Tokyo, where he focused on interventional cardiology and echocardiography with Dr. Tetsu Yamaguchi. Following medical residency and cardiology fellowship, he was appointed Instructor of Medicine/Cardiology at the University of Tokyo in 1992 with Dr. Kiyoshi Kurokawa. In 1995 Dr. Abe decided to pursue his career in medical research and became senior fellow in cardiology and worked with Dr. Bradford C. Berk at University of Washington (UW), Seattle, WA. Dr. Abe received his Ph.D. degree in Medicine/Cardiology from the University of Tokyo in 1998 under the guidance of Drs. Kiyoshi Kurokawa and Yoh Takuwa. He was then recruited to the University of Rochester as an Assistant Professor in 1999, became Tenured Professor in 2011, and Dean’s professor in 2013. In 2014, Dr. Abe joined the faculty of the Department of Cardiology at the University of Texas MD Anderson Cancer Center.
Dr. Abe developed a focused research program during the 15 years since he became an independent researcher. His long-standing interest has always been in signal transduction mechanisms in the cardiovascular system. Recently, Dr. Abe’s group observed a very unique post-translational modification on ERK5, called ERK5-SUMOylation. This ERK5-SUMOylation happens at the K6 and K22 sites on the N-terminal region of ERK5, and inhibits ERK5 transcriptional activity. Although the exact mechanism remains unclear, high glucose, reactive oxygen species, and advanced glycation end products (AGEs) can induce ERK5-SUMOylation and inhibit ERK5 transactivation. This ERK5-SUMOylation and subsequent inhibition of ERK5 transactivation is one of the mechanisms to explain diabetes-mediated endothelial inflammation and dysfunction (Circ. Res., Woo, 2008). While in the heart this modification induces PDE3-ICER feedback loop and subsequent apoptosis (Circ. Res., Shishido, 2008). Therefore, this new post-translational modification of ERK5 could be a very important process to regulate both endothelial and cardiac physiology, especially in diabetic conditions.
Not limited to ERK5-SUMOylation, Dr. Abe’s group also worked on various interesting post-translational modifications including Bcr-mediated PPAR g phosphorylation (Circ. Res., 2009), and MK2-SUMOylation (Blood, 2010). Furthermore, his next study showed that diabetes activates p90RSK, which directly inhibits the transcriptional activity of ERK5, an atheroprotective non-classical MAP kinase. When activated p90RSK associated with ERK5, this association inhibited ERK5 transcriptional activity and up-regulated VCAM-1 expression. In addition, p90RSK directly phosphorylated ERK5 S496 and reduced eNOS expression. This data showed the importance of the p90RSK-ERK5 module in inflammatory responses in ECs and promotes vascular dysfunction (Circulation, 2013). Very recently Dr. Abe’s group found that disturbed flow induced SUMOylation of p53 and ERK5, leading to ECs apoptosis and inflammation, respectively. Reduced expression of SENP2 increased both p53 and ERK5 SUMOylation, hence increased EC dysfunction and inflammation, and accelerated atherosclerosis formation in vivo. These results indicate for the first time that SENP2 function plays an important role in atherosclerosis formation( Circ. Res., 2013 ). Dr. Abe made major contributions in analyzing new aspects of signal transduction pathways, especially for SUMOylation, in cardiovascular pathophysiology.
Dr. Abe received grants from the National Institute of Health and American Heart Association. He was a Fellow of American Heart Association (FAHA), Dean’s Professor at University of Rochester, Established Investigator of the American Heart Association, and was elected to ATVB Special Recognition Award in Vascular Biology. He has written over 100 scientific papers and book chapters, and is a current member of the Editorial Board of the Journal of American College of Cardiology, Circulation Research, Arteriosclerosis, Thrombosis and Vascular Biology, Journal of Molecular and Cellular Cardiology, Journal of Cardiovascular Translational Research, Clinical Science, and Metabolism.
Professor, Department of Cardiology - Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Professor, Texas A&M Health Science Center Institute of Biosciences and Technology, Houston, TX
The major goal of our laboratory is to understand the molecular mechanisms of atherosclerosis formation and heart failure, and to determine the mechanistic underpinning on why diabetes and certain cancer therapy significantly increase the risk of developing cardiovascular diseases (CVD). We have focused on the role of the mitogen-activated protein kinase (MAP) family and have sought the mechanisms responsible for oxidative, hyperglycemia, and hypoxic injury to the vascular endothelium and the heart.
1. Shear stress, SUMOylation, and endothelial dysfunction.
Emerging evidence shows that steady laminar flow (s-flow) exerts atheroprotective while disturbed flow reveals atheroprone effects in vivo. Chronic inflammation and oxidative stress represent some of the pathogenic features in atherosclerosis formation, and flow and shear stress have significant roles in modifying these atherogenic events via regulating “mechanosignal transduction”. s-flow-mediated ERK5 activation increases peroxisome proliferator-activated receptor- g (PPAR g ) activity and demonstrates an anti-inflammatory effect. In contrast, cytokine or high glucose-mediated PKC z activation and novel post-translational modification of ERK5 SUMOylation inhibit ERK5 transcriptional activity, and induce endothelial apoptosis and inflammation. SUMOylation (small ubiquitin-like modifier: SUMO) is analogous to ubiquitination, but SUMO conjugation involves different enzymes including de-SUMOylation enzymes (SENPs). We believe the balance between s-flow and cytokine/high glucose-mediated signaling is the key in regulating the process of atherosclerosis formation. Currently, we are focusing on the roles of the following three kinases, p90RSK, PKC z, and MK2, in s-flow, cytokine/high glucose, and cancer therapy-mediated signaling on endothelial biology.
2. Diabetic and cancer therapy-induced cardiomyopathy
Diabetes is an independent risk factor for both mortality and morbidity after myocardial infarction (MI). A number of clinical studies have shown that the post-MI left ventricular function is significantly worse in diabetic patients compared with non-diabetic patients. In addition, studies strongly indicate that the activation of renin-angiotensin system (RAS) in diabetic patients is a critical factor for developing heart failure after MI (diabetic cardiomyopathy (DMC)). However, what is lacking is a plausible relationship between diabetes and any of the known regulators of myocyte apoptosis known to play a significant role in the post-MI cardiac dysfunction. Our research indicates a critical role of p90RSK and ERK5 kinase activation in this process. We identified three down stream targets of p90RSK: 1) Na + /H + exchanger-1, 2) prorenin-converting enzyme (PRECE), and 3) voltage-gated K+ channels (Kv4.3 and Kv1.5). p90RSK activity was increased in diabetic hearts and accelerates cardiac damage after myocardial infarction.
It has been reported that the chaperone-dependent E3 ubiquitin ligase CHIP (carboxyl terminus of Hsp70-interacting protein) has a strong cellular protective effect. We have also found that ICER could be ubiquitinated and degraded by CHIP, and that ERK5 activation enhances CHIP ubiquitin ligase activity, and subsequent ICER degradation and myocyte apoptosis. We are also investigating the contribution of these pathways in cancer therapy-mediated cardiomyopathy.
3. Determine novel ERK5 activator(s) using High Throughput Screening (HTS)
We have demonstrated the critical role of ERK5 activation in protecting the heart. In addition, it is now clear that laminar shear stress-mediated endothelial protection is due to ERK5 activation. Inhibition of ERK5 transactivation by p90RSK was also observed in EC. These results collectively suggest that activating ERK5 by inhibiting p90RSK may be a novel way for protecting both cardiomyocytes and EC, especially in diabetes and hypercholesterolemia.
Toward the goal of translating this idea into therapy, we initiated a study to look for small molecules capable of activating ERK5. Our major hypothesis is that ERK5 is a “key modulator” which, when activated by statins (especially, pitavastatin and simvastatin), p90RSK specific inhibitor (fmk), and yet unknown novel ERK5 activators, provides cardiovascular protective effects after MI and during the process of atherosclerosis.
Although this line of investigation is still in its early stage, we are excited about the possibility of being able to translate our basic signaling discoveries into developing novel therapeutic strategies for the treatment of heart failure and endothelial dysfunction, especially induced by cancer and cancer therapy.
|1998||University of Tokyo, Tokyo, JPN, PHD, Medicine/Cardiology|
|1987||University of Yamagata, Yamagata, JPN, MD, Medicine|
|1995-1998||Research Fellowship, Cardiology, University of Washington, Seattle, WA|
|1992-1994||Instructor, Internal Medicine and Cardiology, First Department of Internal Medicine, University of Tokyo, Tokyo|
|1989-1992||Clinical Fellowship, Internal Medicine and Cardiology, Mitsui Memorial Hospital, Tokyo|
|1987-1989||Clinical Residency, Internal Medicine, Mitsui Memorial Hospital, Tokyo|
|1987||Medical License (Japan)|
|2013||Dean's Professorship, University of Rochester|
|2010||ATVB Special Recognition Award in Vascular Biology, ATVB|
|2007||Established Investigator Award, American Heart Association|
|2007||Excellence in Research Award, University of Rochester|
|2004||Fellow of the American Heart Association & the Council on Basic Cardiovascular Sciences, American Heart Association|
|2000||Buswell Fellowship Award|
|1999||Buswell Fellowship Award|
|1995||Yamanouchi Foundation for Research on Metabolic Disorders Award, Yamanouchi Foundation|
|1995||Bayer and Japan Heart Foundation Award, Bayer and Japan Heart Foundation|
|1994||Prize in Research, Tokyo Medical Association|
- Le NT, Takei Y, Izawa-Ishizawa Y, Heo KS, Lee H, Smrcka AV, Miller BL, Ko KA, Ture S, Morrell C, Fujiwara K, Akaike M, Abe J. Identification of Activators of ERK5 Transcriptional Activity by High-Throughput Screening and the Role of Endothelial ERK5 in Vasoprotective Effects Induced by Statins and Antimalarial Agents. J Immunol 193(7):3803-15, 2014. e-Pub 2014. PMID: 25187658.
- Heo KS, Cushman HJ, Akaike M, Woo CH, Wang X, Qiu X, Fujiwara K, Abe J. ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis. Circulation 130(2):180-91, 2014. e-Pub 2014. PMID: 25001623.
- Oikawa M, Wu M, Lim S, Knight WE, Miller CL, Cai Y, Lu Y, Blaxall BC, Takeishi Y, Abe J, Yan C. Cyclic nucleotide phosphodiesterase 3A1 protects the heart against ischemia-reperfusion injury. J Mol Cell Cardiol 64:11-9, 2013. e-Pub 2013. PMID: 23988739.
- Smadja-Lamère N, Shum M, Déléris P, Roux PP, Abe J, Marette A. Insulin activates RSK (p90 ribosomal S6 kinase) to trigger a new negative feedback loop that regulates insulin signaling for glucose metabolism. J Biol Chem 288(43):31165-76, 2013. e-Pub 2013. PMID: 24036112.
- Abe J, Berk BC. Atheroprone flow activation of the sterol regulatory element binding protein 2 and nod-like receptor protein 3 inflammasome mediates focal atherosclerosis. Circulation 128(6):579-82, 2013. e-Pub 2013. PMID: 23838164.
- Abe J, Berk BC. Cezanne paints inflammation by regulating ubiquitination. Circ Res 112(12):1526-8, 2013. PMID: 23743222.
- Heo KS, Chang E, Le NT, Cushman H, Yeh ET, Fujiwara K, Abe J. De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis. Circ Res 112(6):911-23, 2013. e-Pub 2013. PMID: 23381569.
- Heo KS, Chang E, Takei Y, Le NT, Woo CH, Sullivan MA, Morrell C, Fujiwara K, Abe J. Phosphorylation of protein inhibitor of activated STAT1 (PIAS1) by MAPK-activated protein kinase-2 inhibits endothelial inflammation via increasing both PIAS1 transrepression and SUMO E3 ligase activity. Arterioscler Thromb Vasc Biol 33(2):321-9, 2013. e-Pub 2012. PMID: 23202365.
- Le NT, Heo KS, Takei Y, Lee H, Woo CH, Chang E, McClain C, Hurley C, Wang X, Li F, Xu H, Morrell C, Sullivan MA, Cohen MS, Serafimova IM, Taunton J, Fujiwara K, Abe J. A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis. Circulation 127(4):486-99, 2013. e-Pub 2012. PMID: 23243209.
- Kim GY, Nigro P, Fujiwara K, Abe J, Berk BC. p62 binding to protein kinase C ζ regulates tumor necrosis factor α-induced apoptotic pathway in endothelial cells. Arterioscler Thromb Vasc Biol 32(12):2974-80, 2012. e-Pub 2012. PMID: 23023376.
- Le NT, Takei Y, Shishido T, Woo CH, Chang E, Heo KS, Lee H, Lu Y, Morrell C, Oikawa M, McClain C, Wang X, Tournier C, Molina CA, Taunton J, Yan C, Fujiwara K, Patterson C, Yang J, Abe J. p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction. Circ Res 110(4):536-50, 2012. e-Pub 2012. PMID: 22267842.
- Nigro P, Abe J, Berk BC. Flow shear stress and atherosclerosis: a matter of site specificity. Antioxid Redox Signal 15(5):1405-14, 2011. e-Pub 2011. PMID: 21050140.
- Shi X, Yan C, Nadtochiy SM, Abe J, Brookes PS, Berk BC. p90 ribosomal S6 kinase regulates activity of the renin-angiotensin system: a pathogenic mechanism for ischemia-reperfusion injury. J Mol Cell Cardiol 51(2):272-5, 2011. e-Pub 2011. PMID: 21609719.
- Heo KS, Lee H, Nigro P, Thomas T, Le NT, Chang E, McClain C, Reinhart-King CA, King MR, Berk BC, Fujiwara K, Woo CH, Abe J. PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation. J Cell Biol 193(5):867-84, 2011. PMID: 21624955.
- Heo KS, Fujiwara K, Abe J. Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction. Circ J 75(12):2722-30, 2011. e-Pub 2011. PMID: 22076424.
|Title:||P90RSK: A Flow Responsive Mediator of Inflammation|
|Title:||Ubiquitin-like Protein Modification in Diabetic Cardiomyopathy|
|Title:||Fluid Shear Stress Signal Transduction in Endothelium|
|Title:||P90RSK-ERK Module, Efferocytosis, and Vulnerable Plaque Formation|
|Title:||Oxidative Stress and Vascular Smooth Muscle Cell Growth|
|Title:||Nuclear beta-catenin Signaling in the Heart|
|Title:||Function and Regulation of Phosphodiesterase in the Heart|
|Title:||Regulation of Lung Autophagy and Inflammation|
|Title:||cART accelerates vascular aging in HIV infected subjects|