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.
As described above, Dr. Abe is a physician-scientist with a 7-year experience as a practicing cardiologist in Japan. Since arriving to the United States 17 years ago, he has devoted his academic career as a basic scientist focused on gaining a deeper understanding of cardiovascular diseases that plague the modern world. The major goal of his 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. Dr. Abe's lab has 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 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-gamma (PPARgamma) activity and demonstrates an anti-inflammatory effect. In contrast, cytokine or high glucose-mediated PKCzeta activation and novel post-translational modification of ERK5 SUMOylation inhibit ERK5 transcriptional activity, and induce endothelial apoptosis and inflammation. 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, PKCzeta, and MK2, in s-flow and cytokine/high glucose-mediated signaling on endothelial biology.
2. 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.
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 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.