Anthony Rosenzweig

Our research effort focuses on the intracellular signaling pathways that control cell survival and inflammation, and how these contribute to cardiovascular disease. To address these issues, we have used a combination of germline and somatic genetic manipulations in the context of pathophysiologically relevant in vitro and in vivo models of diseases including vascular inflammation/atherosclerosis, ischemic heart disease, and heart failure. Highlights of ongoing projects in each of the two major areas of investigation are discussed below.

Vascular diseases and inflammation:

In many vascular conditions including atherosclerosis, transplant arteriosclerosis, and reperfusion injury, leukocytes play a pivotal role in disease progression. For this reason, we are interested in understanding the molecular basis of leukocyte-endothelial cell interactions. Our focus is on the role of specific intercellular signals (such as chemokines) and the intracellular cascades they initiate. Studies on the intracellular mechanisms involved in endothelial activation have recently focused on modulation of NF-B activation through somatic gene transfer and conditional knockout strategies to understand the role of this pathway the cardiovascular system. More recent studies are exploring the role of endothelial progenitor cells in the context of atherosclerosis.

Congestive heart failure:

We have also used somatic gene transfer and germline manipulations to directly test the contribution of specific intracellular pathways to cardiac dysfunction both in isolated cardiomyocytes and whole hearts in vivo. Initial studies focused on calcium handling proteins, while more recent work has characterized intracellular signaling pathways that modulate cardiomyocyte apoptosis and the relationship of these signaling pathways to those controlling cardiomyocyte function. We have been able to demonstrate a critical role for specific kinases such as PI3-kinase and Akt (Protein Kinase B) in preserving the survival and function of cardiomyocytes both in vitro and in vivo, as well as the importance of Akt-independent pathways in the context. Translational implications of these findings are also being explored in efforts to optimize cardioprotection through expression of secreted ligands that mediate both autocrine and paracrine benefits. Similar strategies may have relevance to optimize survival and function of progenitor cell populations being considered for potential regenerative therapies in the heart.