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Thomas Jefferson University - Andrea Eckhart, Ph.D.
Andrea Eckhart, Ph.D.

Thomas Jefferson University
Jefferson Medical College
Associate Professor of Medicine
Center for Translational Medicine
Director of the Eugene Feiner Laboratory for Vascular Biology and Thrombosis
Mailing Address
Center for Translational Medicine
1025 Walnut Street, Rm 309 College Bldg
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: (215) 955-9992
Andrea.Eckhart@jefferson.edu
Expertise and Research Interests
Hypertension is a prevalent disease and the cause of the majority of cases is unknown. Chronic hypertension exacerbates diseases such as heart failure and atherosclerosis ultimately leading to increased morbidity and mortality. Therefore, a better understanding of the mechanism underlying this disease needs to be further studied. Blood pressure (BP) is established by a number of different inputs, however, the component that has the greatest impact on BP is the radius of the blood vessel. Blood vessel diameter is established by the constriction status of the vascular smooth muscle (VSM). It is primarily determined by neurotransmitters and hormones binding to G protein-coupled receptors (GPCRs). Following stimulation of a GPCR, there are feedback mechanisms that diminish GPCR signaling. A family of proteins called GPCR kinases (GRKs) phosphorylates agonist-bound GPCRs and subsequently, the GPCR no longer signals through its classically identified G protein. GRK2 and GRK5 are elevated in human and animal models of hypertension.

Dr. Eckhart's laboratory has made transgenic mice with overexpression of either GRK2 or GRK5 in VSM. Overexpression of either of these proteins is sufficient to increase BP. Dr. Eckhart has begun to investigate the mechanisms underlying this increase in BP. It appears that although the phosphorylation of certain GPCRs by the GRKs desensitizes classical signaling, it also reveals new signaling paradigms. Dr. Eckhart has found that the b-adrenergic receptors, that normally mediate vasodilation via a Gs protein, switch to preferring Gi. This switching phenomenon changes a receptor that normally mediates dilation into a receptor, that when stimulated, now mediates constriction. This has profound effects on the maintenance of BP homeostasis. Her laboratory is currently investigating whether this "switching" phenomenon also occurs for other G protein-coupled receptors.

In addition to understanding the changes in molecular signaling that occur during hypertension, Dr. Eckhart's laboratory is also interested in developing antihypertensive therapeutic strategies. GPCRs that signal via the Gq protein mediate vasoconstriction. Although there are inhibitors of particular receptors, there are no drugs available that inhibit signaling through all Gq-coupled receptors in a class specific manner, thus necessitating treatment regimens that require multiple drugs. The lab has developed a peptide inhibitor of all Gq-mediated signaling and expressed it in the VSM of mice. The expression of this peptide in the VSM was sufficient to attenuate developed hypertension suggesting that GqI could be a powerful molecule to combat high BP. Dr. Eckhart is investigating the mechanisms underlying this prevention of hypertension and attempting to generate other class-specific peptide inhibitors in an attempt to design better drug therapies.
Publications
  • Cohn HI, Xi Y, Pesant S, Harris DM, Hyslop T, Falkner B, Eckhart AD. G protein-coupled receptor kinase 2 (GRK2) expression and activity are associated with blood pressure in black Americans. Hypertension. 54:71-76, 2009.

  • Harris DM, Chen X, Pesant S, Cohn HI, MacDonnell SM, Boucher M, Vinge LE, Raake P, Moraca SR, Li D, Most P, Houser SR, Koch WJ, Eckhart AD. Inhibition of angiotensin II Gq signaling augments beta-adrenergic receptor mediated effects in a renal artery stenosis model of high blood pressure. Journal of Molecular and Cellular Cardiology, 46:100-107, 2009.

  • Zhou RH, Pesant S, Cohn HI, Soltys S, Koch WJ, Eckhart AD. Negative regulation of VEGF signaling in human coronary artery endothelial cells by G protein-coupled receptor kinase 5. Clinical and Translational Science. 2:57-61, 2009.

  • Cohn HI, Harris DM, Pesant S, Pfeiffer M, Zhou R, Koch W, Dorn GW, Eckhart AD. Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances alpha-1DAR constriction. American Journal of Physiology. 295:H1695-H1704, 2008.

  • Harris DM, Cohn HI, Pesant S, Eckhart AD. GPCR signaling in hypertension: role of GRKs. Clinical Science. 115:79-89, 2008.

  • Martini JS, Raake P, Vinge LE, DeGeorge B Jr, Chuprun JK, Harris DM, Gao E, Eckhart AD, Pitcher JA, Koch WJ. Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proceedings of the National Academy of Sciences USA. 105:12457-12462, 2008.

  • Ohtsu H, Higuchi S, Shirai H, Eguchi K, Suzuki H, Hinoki A, Brailoiu E, Eckhart AD, Frank GD, Eguchi S. Central role of Gq in the hypertrophic signal transduction of angiotensin II in vascular smooth muscle cells. Endocrinology. 149:3569-3575, 2008.

  • Raake PW, Vinge LE, Gao E, Boucher M, Rengo G, Chen X, Degeorge BR Jr, Matkovich S, Houser SR, Most P, Eckhart AD, Dorn GW 2nd, Koch WJ. G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circulation Research. 103:413-422, 2008.

  • Pleger S, Harris DM, Shan C, Vinge L, Chuprun JK, Berzins B, Pleger W, Druckman C, Volkers M, Heierhorst J, Oie E, Remppis A, Katus HA, Scalia R, Eckhart AD, Koch WJ, Most P. Endothelial S100A1 modulates vascular function via nitric oxide. Circulation Research, 102:786-794, 2008.

  • DeGeorge Jr BR, Gao E, Boucher M, Vinge LE, Martini JS, Raake PW, Chuprun JK, Harris DM, Kim GW, Soltys S, Eckhart AD, Koch WJ. Targeted inhibition of inhibitory G protein a subunit class Gi signaling enhances susceptibility to apoptotic cell death in response to ischemic stress. Circulation, 117:1378-1387, 2008.

  • Mahadev K, Wu X, Donnelly S, Ouedraogo R, Eckhart AD, Goldstein BJ. Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells. Cardiovascular Research. 78:376-384 2008.

  • Zhou R, Pesant S, Cohn HI, Eckhart AD. Enhanced Sterol Response Element-Binding Protein in Postintervention Restenotic Blood Vessels Plays an Important Role in Vascular Smooth Muscle Proliferation. Life Sciences. 82:174-181, 2008.

  • Harris DM, Cohn HI, Pesant S, Zhou R-H, Eckhart AD. Vascular Smooth Muscle Gq Signaling is Involved in High Blood Pressure in Both Induced Renal and Genetic Vascular Smooth Muscle-Derived Models of Hypertension. Am J Physiol. 293:H3072-H3079, 2007.

  • Macdonnell SM, Kubo H, Harris DM, Chen X, Berretta R, Barbe MF, Kolwicz S, Reger PO, Eckhart A, Renna BF, Koch WJ, Houser SR, Libonati JR. Calcineurin Inhibition Normalizes b-Adrenergic Responsiveness in the Spontaneously Hypertensive Rat. Am J Physiol. 293:H3122-H3129, 2007.

  • Giangrande PH, Zhang JX, Tanner A, Eckhart AD, Rempel RE, Andrechek ER, Layzer JM, Keys JR, Hagen PO, Nevins JR, Koch WJ, Sullenger BA. Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia. Proc. Natl. Acad. Sci. U.S.A. 104:12988-12993, 2007.

  • Gao E, Boucher M, Chuprun JK, Zhou RH, Eckhart AD, Koch WJ. Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart. Am J Physiol. 293: H60-68, 2007.

  • Lymperopoulos A, Rengo G, Funakoshi H, Eckhart AD, Koch WJ. Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nature Medicine. 13:315-323, 2007.

  • Pleger ST, Most P, Boucher M, Soltys S, Chuprun JK, Pleger W, Gao E, Dasgupta A, Rengo G, Remppis A, Katus HA, Eckhart AD, Rabinowitz JE, Koch WJ. Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue. Circulation. 115:2506-2515, 2007.

  • Kim J, Keys JR, Eckhart AD. Vascular smooth muscle migration and proliferation in response to lysophosphatidic acid (LPA) is mediated by LPA receptors coupling to Gq. Cell Signal 18:1695-1701, 2006.

  • Harris DM, Eckhart AD, Koch WJ. Gaq and its Aktions. J Mol Cell Cardiol 40:589-592, 2006.

  • Most P, Seifert H, Gao E, Funakoshi H, Volkers M, Heierhorst J, Remppis A, Pleger ST, DeGeorge BR Jr, Eckhart AD, Feldman AM, Koch WJ. Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction. Circulation. 114:1258-1268, 2006.

  • Keys JR, Zhou R-H, Harris DM, Druckman CA, Eckhart AD. Vascular smooth muscle overexpression of G protein-coupled receptor kinase 5 elevates blood pressure which segregates with sex and is dependent on Gi-mediated signaling. Circulation 112:1145-1153, 2005.

  • Mifune M, Ohtsu H, Suzuki H, Nakashima H, Brailoiu E, Dun NJ, Frank GD, Inagami T, Higashiyama S, Thomas WG, Eckhart AD, Dempsey PJ, Eguchi S. G protein coupling and second messenger generation are indispensable for a metalloprotease-dependent HB-EGF shedding through angiotensin II type-1 receptor. J Biol Chem. 280:26592-26599, 2005

  • Pleger ST, Remppis A, Heidt B, Volkers M, Gao E, Chuprun JK, Szabo G, Weichenhan, Muller O, Eckhart AD, Katus, HA, Koch WJ, Most P. S100 gene therapy preserves in vivo cardiac function after myocardial infarction. Mol. Ther. [Epub ahead of print], 2005

  • Tevaearai HT, Walton GB, Keys JR, Koch WJ, Eckhart AD. Acute ischemic cardiac dysfunction is attenuated via gene transfer of a peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1). J Gene Med. 9:1172-1177, 2005.

  • Most P, Pleger ST, Volkers M, Heidt B, Boerries M, Weichenhan D, Loffler E, Janssen PML, Eckhart AD, Martini J, Williams ML, Katus HA, Remppis A, Koch WJ. Cardiac adenoviral S100A1 gene delivery rescues failing myocardium. J Clin Invest. 114:1550-1563, 2004.

Individual Expertise profile of Andrea Eckhart, Ph.D., Copyright © Andrea Eckhart, Ph.D..
Last Updated by Andrea Eckhart, Ph.D. : Tuesday, June 30, 2009 11:32:01 AM



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