ABE Lab

In the last four years, I have been interested in 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 our 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. We 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, we are investigating the role of p90RSK and ERK5 kinases in heart damage and atherosclerosis by using genetically manipulated animals (transgenic mice). Our 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. We have developed a novel hypothesis based on data from our laboratory that p90 ribosomal S6 kinase (p90RSK) is a physiological substrate of PKCb2, and that Troponin I (TnI) phosphorylation by p90RSK contributes to decreased cardiac function in diabetes. We 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-g (PPARg) ligands inhibit adhesion molecule expression in activated endothelial cells and significantly reduce monocyte/macrophage homing to atherosclerotic plaques. We found that steady laminar flow activates ERK5, and increases PPARg transcriptional activation. In addition, hinge-helix1 region of PPARg fragment specifically disrupts ERK5/PPARg interaction and inhibits activated ERK5-mediated PPARg activation, supporting the specific role of ERK5 and PPARg interaction in laminar flow-mediated anti-inflammatory effect. Based on our exciting preliminary data, we hypothesize that laminar flow acts as an anti-inflammatory modulator by increasing PPARg transcriptional activity, and decreasing VCAM-1 expression in endothelial cell. We will determine endothelial ERK5, JNK, NF-kB, 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 MEK5a or ERK5 knock out in LDLR-/- knock out (KO) mice, which has been characterized by atherosclerosis formation. We anticipate that pioglitazone and/or CA-MEK5a inhibits and ERK5 KO will promote atherosclerosis formation.