Jonas Galper, MD, PhD'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.
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.
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.
1. Park HJ, Georgescu SP, Du C, Madias C, Aronovitz MJ, Welzig CM, Wang B, Begley U, Zhang Y, Blaustein RO, Patten RD, Karas RH, Van Tol HH, Osborne TF, Shimano H, Liao R, Link MS, Galper JB. Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP. Journal of Clinical Investigation 2008;118(1):259-271. PubMed Abstract
2. Park HJ, Zhang Y, Georgescu SP, Johnson KL, Kong D, Galper JB. Human umbilical vein endothelial cells and human dermal microvascular endothelial cells offer new insights into the relationship between lipid metabolism and angiogenesis. Stem Cell Reviews 2006;2(2):93-102. PubMed Abstract
3. Park HJ, Ward SM, Desgrosellier JS, Georgescu SP, Papageorge AG, Zhuang X, Barnett JV, Galper JB. Transforming growth factor β regulates the expression of the M² muscarinic receptor in atrial myocytes via an effect on RhoA and p190RhoGAP. Journal of Biological Chemistry 2006;281(29):19995-20002. PubMed Abstract
4. Tang D, Park HJ, Georgescu SP, Sebti SM, Hamilton AD, Galper JB. Simvastatin potentiates tumor necrosis factor ∝-mediated apoptosis of human vascular endothelial cells via the inhibition of the geranylgeranylation of RhoA. Life Sciences 2006;79(15):1484-1492. PubMed Abstract
5. Welzig Cm, Shin D-G, Park H-J, Kin Y-J, Saul JP, Galper JB. Lipid Loweringby Pravastatin Increases Parasympathetic Modulation of Heart Rate: Gi2 as a Possible Molecular Marker of Parasympathetic Responsiveness. Circulation. 2003;108: 2743-2746, 2003. PubMed Abstract
6. Park H-J, Kong D, Iruela-Arispe L, Begley U, Tang D, Galper JB. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA. Circ. Res. 2002;91:143-150. PubMed Abstract
7. Park, H-J, Begley U, Kong D, Yu H, Yin L, Hillgartner FB, Osborne TF, Galper JB. Role of sterol regulatory element binding proteins in the regulation of Galphai2 expression in cultured atrial cells. Circ. Res. 2002;91:32-37. PubMed Abstract
8. Gadbut AP, Wu L, Tang, D, Papageorge A, Watson, JA, Galper JB. Low density lipoproteins regulate levels of functional RAS in embryonic chick heart cells: A role for RAS in regulating the expression of muscarinic receptors and G-proteins. The Embo J 1997;16;7250-7260. PubMed Abstract
9. Haigh LS, Leatherman GF, O'Hara DS, Smith TW, Galper JB. Effects of low density lipoproteins and mevinolin on cholesterol content and muscarinic responsiveness in cultured chick atrial cells: Regulation of levels of muscarinic receptors and guanine nucleotide regulatory proteins. J Biol Chem 1988; 263:15608-15618. PubMed Abstract
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Jonas Galper, MD, PhD
Principal Investigator, Laboratory of Lipid Metabolism and Cardiovascular Signaling, and Professor of Medicine, Tufts University School of Medicine
Dr. Galper received his BA in chemistry from Harvard College. He received his MD and PhD from the Albert Einstein College of Medicine and did his house staff training at New England Medical Center (now Tufts Medical Center). He served as a Clinical Associate at the National Heart Lung and Blood Institute at the National Institutes of Health. He received his fellowship training in Cardiology at the Peter Bent Brigham Hospital and became a faculty member at the Harvard Medical School and attending physician at the Brigham and Women’s Hospital as an instructor, assistant professor and associate professor. He is an Established Investigator of the American Heart Association and has served on the editorial boards of Circulation Research and the Journal of Molecular and Cellular Cardiology. Dr. Galper has a program for the study of the role of lipids in signaling in the cardiovascular system and is involved in collaborations with Drs. Richard Karas and Mark Estes.
Hongwei Jin, PhD
Bonnie Wang, MD
Bo Wang received her M.D. degree from the Kunming Medical College and was an Assistant Professor/Physician-in-charge in China (1st Affiliated Hospital of Kunming Medical College from 1990-2001). Prior to joining the MCRI she worked as a Research Associate in CV Research labs at BU, BWH and BIDMC. As a Research Associate in the Galper lab, Dr. Wang is working with an abdominal aortic aneurysm mouse model.
Yali Zhang, MD, PhD
Yali Zhang earned her MD from Tianjin Medical University, China in 1997. After receiving her PhD in Pharmacology from Peking University Health Science Center (Beijing Medicine University) in China, she joined Dr. Galper's lab in the MCRI as a postdoctoral research fellow in 2005. She is currently studying the role of lipid metabolism in angiogenesis and atonomic responsiveness using in vitro and in vivo models.
Dionne Bradford joined the MCRI in June 2006 as a Research Administrator. In this role she is responsible for identifying new funding opportunities, submission of grant proposals, and all post-award including financial tracking. Additionally, Dionne works closely with the Director of Administration and Finance on matters relating to research facilities, human resources, technology transfer, and compliance issues. Prior to joining the MCRI, Dionne worked for the CBR Institute/Harvard Medical School. Dionne is an alumna of the University of Massachusetts.