Principal Investigator: Ravichandran Ramasamy, PhD
Background & Research Interests
The main focus of my research effort has been to understand the metabolic basis of ischemic injury and heart failure in diabetics. In this context, our work has led to the novel finding that the glucose metabolizing enzyme, aldose reductase, assumes a critical role in the pathogenesis of myocardial ischemic injury in diabetics and non-diabetics. Aldose reductase, both the first and rate-limiting enzyme in the polyol pathway, has been implicated in numerous diabetic complications.
Our laboratory demonstrated that substrate flux via aldose reductase adversely impacts cardiac glucose metabolism and is a mediator of ischemic injury. The work of our laboratory provided the insight into a direct link between glucose flux via aldose reductase and ion homeostasis in cardiac tissue. In subsequent studies, we provided the missing link in the ischemic heart, that is, the means by which biochemical/metabolic disturbances recruit signal transduction pathways that trigger perturbation, mitochondrial dysfunction, and cell death in the heart.
Currently, we have focused on the ability of aldose reductase to act independent of cytosolic redox changes. In this context, studies are in progress to link flux via aldose reductase to (a) generation of advanced glycation end product (AGE) precursors, thereby activating AGE-RAGE pathway dependent signaling for cellular injury, and (b) activating nuclear transcription factors, such as HIF-1α, that are critical determinants of cell survival.
In our quest for exploring the impact of aldose reductase comprehensively in diabetic cardiovascular disease, we have embarked on studies investigating flux via aldose reductase in influencing atherosclerotic lesion formation and femoral artery denudation injury. Studies are in progress to dissect the mechanisms by which aldose reductase promotes/accelerates atherogenesis.
Driven by the complexities of mechanisms that underlie myocardial ischemic injury and diabetic cardiovascular complications, the goal of my laboratory is to elucidate the importance of aldose reductase, and AGE-RAGE in mediating ischemic injury, metabolic imbalances, heart failure and atherosclerosis. It is my hope and expectation that interventions that block these key pathways will be employed in the near future to treat patients with evolving myocardial infarction and diabetic cardiovascular complications.