Dr. Galper’s laboratory focuses on the role of lipid metabolism in the regulation of cell signaling in the heart and vasculature. He is studying the molecular basis for cardiac risk factors and the relationship between lipid lowering, hypertension and angiogenesis, both in an in vivo model for tube formation by endothelial cells, and in a mouse model for atherosclerosis. He is also studying the role of lipids, GTP binding proteins and the regulation of gene expression by sterol responsive transcription factors in the control of the autonomic response of the heart and the development of arrhythmias in both cell culture and mouse models. His clinical studies focus on the role of lipid lowering in regulating the autonomic response of the heart in patients treated with statins and its relationship to the development of cardiac arrhythmias and diabetic autonomic neuropathy.
Research Focus and Highlights
The Galper Laboratory has had a long standing interest in the role of GTP binding proteins in the regulation of cardiac physiology during cardiac development, in response to innervation of the heart and in response to growth factors. We developed an in vitro model for the study of the effects of lipid lowering on cardiomyocyte physiology. We made the surprising observation that lipid lowering markedly increased the response of atrial myocytes to parasympathetic stimulation. This increase in responsiveness was associated with an increase in the expression of the genes coding for proteins which play a role in the parasympathetic response pathway in the heart: the M2 muscarinic receptor; the hetrotrimeric G-Protein, Ga i2; and the inward rectifying K channel, GIRK1/GIRK4. We demonstrated that this increase in gene expression was dependent on the activation of the small GTP binding protein Ras and demonstrated a new lipid dependent mechanism for the regulation of the activity of Ras and other small GTP binding proteins. Current studies focus on the mechanism for lipid regulation of Ras and Rho dependent kinases and their role in regulating expression of genes involved in signaling in the heart and vasculature.
Role of lipid metabolism in the regulation of the autonomic response of the heart. Based of the fact that lipid lowering regulates the expression and function of sterol responsive transcription factors, we are investigating the interaction of these transcription factors and small GTP binding proteins in regulating specific downstream kinase pathways that control expression and function of genes involved in the response of the heart to autonomic stimulation using cultured myocytes and EKG and electrophysiology studies in genetically manipulated mice. Since the parasympathetic responsiveness of the heart plays a role in the protection of the heat from arrhythmias, the long term goal of these studies is to determine the relationship between the regulation of sterol responsive transcription factors and the genesis and treatment of arrhythmias.
The relationship between Cholesterol metabolism and angiogenesis: the role of statins. We have demonstrated that statins regulate angiogenesis both in vivo and in vitro via the control of the activity of the small GTP binding protein Rho. Our current studies deal with the relationship between hypertension, hyperlipidemia and angiogenesis and the role of statins in regulating the progression of atherosclerotic lesions in a mouse model. We are studying the mechanism of angiotensin II mediated angiogenesis and the interaction of Ang II with proangiogenic growth factors and transcription factors such as HIF1a in endothelial cells and smooth muscle cells.
Clinical Studies: Effect of lipid lowering by statins on the parasympathetic response of the heart and the development of arrhythmias. These studies represent a direct extrapolation of our in vitro observations on the role of lipids in the regulation of the parasympathetic response. Studies include the effect of statins and lipid lowering on ventricular ectopy and arrhythmias in mice. Also in progress is a double blind crossover study of patients randomized to simvastatin and pravastatin using heart rate variability analysis to determine effects on parasympathetic responsiveness as well as measurements of cardiac ectopy. Direct studies of the effects of statins and lipid lowering on arrhythmias and diabetic autonomic neuropathy are planned.