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.
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.
| Kumar, Nitin; Liao, Tang-Dong; Romero, Cesar A et al. (2018) Thymosin ?4 Deficiency Exacerbates Renal and Cardiac Injury in Angiotensin-II-Induced Hypertension. Hypertension 71:1133-1142 |
| Bryson, Timothy D; Gu, Xiaosong; Khalil, Remonda M et al. (2018) Overexpression of prostaglandin E2 EP4 receptor improves cardiac function after myocardial infarction. J Mol Cell Cardiol 118:1-12 |
| Cerniello, Flavia M; Carretero, Oscar A; Longo Carbajosa, Nadia A et al. (2017) MAS1 Receptor Trafficking Involves ERK1/2 Activation Through a ?-Arrestin2-Dependent Pathway. Hypertension 70:982-989 |
| Ren, YiLin; Janic, Branislava; Kutskill, Kristopher et al. (2016) Mechanisms of connecting tubule glomerular feedback enhancement by aldosterone. Am J Physiol Renal Physiol 311:F1182-F1188 |
| 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: |
| Ramseyer, Vanesa D; 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 310:F748-F754 |
| 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 |
| Gu, Xiaosong; Xu, Jiang; Zhu, Liping et al. (2016) Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail 9: |
| Kumar, Nitin; Nakagawa, Pablo; Janic, Branislava et al. (2016) The anti-inflammatory peptide Ac-SDKP is released from thymosin-?4 by renal meprin-? and prolyl oligopeptidase. Am J Physiol Renal Physiol 310:F1026-34 |
| Zhu, Liping; Yang, Xiao-Ping; Janic, Branislava et al. (2016) Ac-SDKP suppresses TNF-?-induced ICAM-1 expression in endothelial cells via inhibition of I?B kinase and NF-?B activation. Am J Physiol Heart Circ Physiol 310:H1176-83 |
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