Jun-ichi Abe, M.D., Ph.D.
Professor - Professor - Department of Medicine, Aab Cardiovascular Research Institute
PhD | Internal Medicine/Cardiology | Japan-U Tokyo Fac Med
MD | Medicine | Japan - Yamagata University
I am a physician-scientist with a 7-year experience as a practicing cardiologist in Japan. Since arriving to the United States 17 years ago, I have devoted my academic career as a basic scientist focused on gaining a deeper understanding of cardiovascular diseases that plague the modern world. 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 significantly increases the risk of cardiac mortality. 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.
- Shear stress, SUMOylation, and endothelial dysfunction.
Emerging evidences show 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 (PPARg) activity and demonstrates an anti-inflammatory effect. In contrast, cytokine or high glucose-mediated PKCz 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, PKCz, and MK2, in s-flow and cytokine/high glucose-mediated signaling on endothelial biology.
- Diabetic 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 also have 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.
- 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 DM 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 it’s 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.
- Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction. Heo KS, Fujiwara K, Abe J. Circ J. 2011 Nov 25;75(12):2722-30.
- PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation. 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., J Cell Biol. 2011 May 30;193(5):867-84.
- p90 ribosomal S6 kinase regulates activity of the renin-angiotensin system: a pathogenic mechanism for ischemia-reperfusion injury. Shi X, Yan C, Nadtochiy SM, Abe J, Brookes PS, Berk BC. J Mol Cell Cardiol. 2011 Aug;51(2):272-5.
- Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E-deficient mice. Nigro P, Satoh K, O'Dell MR, Soe NN, Cui Z, Mohan A, Abe J, Alexis JD, Sparks JD, Berk BC. J Exp Med. 2011 Jan 17;208(1):53-66.
- MK2 SUMOylation regulates actin filament remodeling and subsequent migration in endothelial cells by inhibiting MK2 kinase and HSP27 phosphorylation. Chang E, Heo KS, Woo CH, Lee H, Le NT, Thomas TN, Fujiwara K, Abe J. Blood. 2011 Feb 24;117(8):2527-37.
Jun-ichi Abe, M.D., Ph.D.
University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box CVRI
Rochester, New York 14642
Admin. Office: (585) 276-9800
Research Assistant Professor
Research Assistant Professor