Uncontrolled hypertension (HTN) is a major cause of end organ damage (EOD) and a risk factor for cardiovascular morbidity and mortality. Although prostaglandin E2 (PGE2) was historically thought to be a mediator of inflammation, more recent evidence suggests that it may be pro or anti-inflammatory;depending on the involvement of specific PGE2 EP receptor sub-types that signal through divergent signaling pathways. We previously reported that aged male mice lacking the EP4 receptor on cardiomyocytes develop heart failure characterized by reduced ejection fraction, left ventricle dilatation and fibrosis;coupled with elevated expression of chemokines (fractalkine and MCP-5) in the left ventricle. This proposal examines whether the protective and anti-inflammatory effects of PGE2 via EP4 are mediated by reduced fractalkine and MCP-5. It tests the general hypothesis that EP4, activated by PGE2, reduces the EOD that occurs in Angiotensin II (Ang ll)-dependent hypertension and myocardial infarction (Ml) by inhibiting the production and/or release of the inflammatory chemokines fractalkine and MCP-5.
Aim I will study whether PGE2 via its EP4 receptor reduces production and/or secretion of fractalkine and MCP-5 via its EP4 receptor and cAMP in cardiac myocytes and fibroblasts and opposes the deleterious effects of Ang II.
Aim II will study whether EP4 dependent reductions in fractalkine and/or MCP-5 improve cardiac function both in vivo and in vitro.
Aim II will study whether PGE2 via its EP4 receptor and inhibition of fractalkine and/or MCP-5 synthesis and/or release prevents EOD by reducing infiltration of inflammatory cells into the myocardium in models of Ang ll- dependent HTN and myocardial infarction (Ml). The proposal will utilize a novel mouse model coupled with state-of-the art molecular techniques to address these aims. These studies are of utmost importance in determining the role of PGE2 and EP4 in cardiac hypertrophy and EOD. Project II is closely related to: 1) Projects I and III which also study the pathogenesis of EOD;2) Project IV which also studies A T I receptors and superoxide;and 3) Project III which also studies arachidonic acid metabolites. Project II will use all 4 Cores.

Public Health Relevance

If the proposed aims are achieved, we will understand the role of PGE2 and EP4 in the maintenance of cardiac function. The protective and anti-inflammatory effect of PGE2 via EP4 is of great significance given the number of people taking NSAIDS for a variety of conditions. Our study could lead to development of new therapeutic strategies for the treatment of hypertension, myocardial infarction, and end organ damage.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL028982-31A1
Application #
8460616
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-02-15
Budget End
2014-01-31
Support Year
31
Fiscal Year
2013
Total Cost
$331,192
Indirect Cost
$105,123
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Gonzalez-Vicente, Agustin; Saikumar, Jagannath H; Massey, Katherine J et al. (2016) Angiotensin II stimulates superoxide production by nitric oxide synthase in thick ascending limbs. Physiol Rep 4:
González, Germán E; Rhaleb, N-E; D'Ambrosio, Martin A et al. (2016) Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 311:H1287-H1296
Ren, Yilin; Janic, Branislava; Kutskill, Kristopher et al. (2016) Mechanisms of Connecting Tubule Glomerular Feedback Enhancement by Aldosterone. Am J Physiol Renal Physiol :ajprenal.00076.2016
Gu, Xiaosong; Xu, Jiang; Zhu, Liping et al. (2016) Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail 9:
Zhu, Liping; Yang, Xiao-Ping; Janic, Branislava et al. (2016) Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation. Am J Physiol Heart Circ Physiol 310:H1176-83
Ramseyer, Vanesa Daniela; Ortiz, Pablo A; Carretero, Oscar A et al. (2016) Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs. Am J Physiol Renal Physiol :ajprenal.00473.2015
Cerrato, Bruno D; Carretero, Oscar A; Janic, Brana et al. (2016) Heteromerization Between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences. Hypertension 68:1039-48
Worou, Morel E; Liao, Tang-Dong; D'Ambrosio, Martin et al. (2015) Renal protective effect of N-acetyl-seryl-aspartyl-lysyl-proline in dahl salt-sensitive rats. Hypertension 66:816-22
Peng, Hongmei; Sarwar, Zeyd; Yang, Xiao-Ping et al. (2015) Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction. Hypertension 66:582-9
Monzon, Casandra M; Garvin, Jeffrey L (2015) Nitric oxide decreases the permselectivity of the paracellular pathway in thick ascending limbs. Hypertension 65:1245-50

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