Andrea Eckhart, Ph.D.

Contact Dr. Eckhart

Center for Translational Medicine
1025 Walnut Street, Suite 309
Philadelphia, PA 19107

(215) 955-9992
(215) 503-5731 fax

Degree
Ph.D. University of North Carolina 1997

University Appointment
Associate Professor

Research and Clinical 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

Most Recent Peer-reviewed Publications

1. G Protein-coupled receptor kinase 2 expression and activity are associated with blood pressure in black americans
2. Inhibition of angiotensin II Gq signaling augments β-adrenergic receptor mediated effects in a renal artery stenosis model of high blood pressure
3. Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances α1D-adrenergic receptor constriction
4. Inhibition of angiotensin II Gq signaling augments β-adrenergic receptor mediated effects in a renal artery stenosis model of high blood pressure
5. Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes
6. G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure.
7. GPCR signalling in hypertension: Role of GRKs
8. Central role of Gq in the hypertrophic signal transduction of angiotensin II in vascular smooth muscle cells
9. Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells
10. Endothelial S100A1 modulates vascular function via nitric oxide
11. Targeted inhibition of cardiomyocyte Gi signaling enhances susceptibility to apoptotic cell death in response to ischemic stress
12. Enhanced sterol response element-binding protein in postintervention restenotic blood vessels plays an important role in vascular smooth muscle proliferation
13. Calcineurin inhibition normalizes β-adrenergic responsiveness in the spontaneously hypertensive rat
14. Vascular smooth muscle Gq signaling is involved in high blood pressure in both induced renal and genetic vascular smooth muscle-derived models of hypertension
15. Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia
16. Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart
17. Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue
18. Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure
19. Vascular smooth muscle migration and proliferation in response to lysophosphatidic acid (LPA) is mediated by LPA receptors coupling to Gq
20. Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction

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