Prasanna LAB
Finding Cure for Heart Diseases

Research in Prasanna's laboratory is supported through funds from National Institutes of Health (NIH-R01) and American Heart Association (AHA).

Our Goal

Overall research focus in my laboratory is to study mechanisms of cardiovascular diseases and develop novel therapeutic strategies to enhance stem cell differentiation and function and promote cardiac regeneration and repair. Current scientific work in our laboratory involves two broad areas of research. I) To understand the molecular mechanisms by which diabetes increases the risk for coronary artery disease and the resulting pathophysiological consequences. II) to define factors that affect cardiovascular regeneration in diabetes, in addition to exploring newer and ideal stem cells and biomaterials for therapeutics after cardiac ischemic injury.

Over the years, our laboratory has developed a strong scientific background and expertise in cardiovascular pathophysiology, molecular and cellular signaling mechanisms and extensive hands-on experience and understanding of mouse surgical models of heart failure (MI, TAC) and bone marrow transplantation systems. Our approach involves use of pharmacological, biochemical, molecular, cellular and physiological techniques including transgenic mice and relevant surgical models to address fundamental questions about the mechanisms of cardiovascular disease progression in diabetes, and to develop potential therapeutic approaches to intervene the diseases.

It is our hope and expectation that these studies will identify new targets that will aid in development of future drugs and new therapies for prevention and treatment of cardiovascular disease complications in diabetes.




Stem cells, cardiovascular regeneration and repair

Acute ischemic injury and chronic cardiomyopathies lead to permanent loss of cardiac tissue. Transplantation of bonemarrow (BM)-derived progenitor cells has the potential to improve cardiac function after ischemic injury. However, number and functional capacity of these cells are impaired in diabetes. Our objectives are to determine the impact of the diabetic milieu (high glucose and fatty acids) on progenitor cell biology and function and their contribution to myocardial repair in response to ischemic injury.

Our on-going studies to investigate the effect of heart failure (HF) on microRNA dysregulation and human CD34+ cells (currently in clinical trials) has yielded valuable scientific information. Human cardiac biopsies from patients with HF showed significant increases in miR-377 expression compared with nonfailing control hearts. In vitro over-expression of miR-377 in hCD34+cells significantly diminished their ability to form vascular tubes and secrete proangiogenic proteins. Most importantly, in a mouse model of myocardial ischemia-reperfusion, transplantation of miR-377 knockdown hCD34+cells into ischemic myocardium promoted their angiogenic ability, attenuating cardiac fibrosis and improved left ventricular function.
Work published in Journal of the American College of Cardiology, 66(20), 17–24 November 2015, Pages 2214–2226


Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.



Diabetes impairs phagocytosis of dead cell

Patients with diabetes and obesity have increased risk for cardiovascular disease. Efferocytosis, a process of removal of dead cells by phagocytosis (like macrophages) after physiological and/or pathological apoptotic cell death, is crucial for tissue homeostasis. Aberrant clearance leads to progression of a number of human chronic inflammatory diseases such as autoimmune and neurological disorders, inflammatory lung diseases or atherosclerosis. We are studying the influence of diabetes on macrophage dysfunction and clearance of dead cells and its implications on heart disease. We recently discovered that diabetes has a negative influence on this fundamental cellular process.
Read more about this discovery

In summary, we show that diabetes-induced decrease in miR-126 expression results in upregulation of ADAM9 expression that in-turn leads to proteolytic cleavage of MerTK and formation of inactive sMer. The resulting decrease in MerTK phosphorylation (inactivation) leads to reduced downstream cytoskeletal signaling required for engulfment and thus decreases efferocytosis of apoptotic cells and lower inflammation resolution, which eventually results in defective organ repair. This is termed as “not ready to eat” signal of macrophages in the diabetic conditions. Image on the right depicts that overexpression of miR-126 suppresses ADAM9 expression, which in turn rescues efferocytosis in diabetic conditions. This sends “ready to eat signal” from the miR-126 overexpressed macrophages in diabetic conditions. This eventually results in improved organ repair and regeneration.
Published in Scientific Reports, 2016 (6); Article number: 36207