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Angiotensin II (ANG II) plays a key role in regulating blood pressure and inflammation. Prostaglandin E 2 (PGE 2 ) signals through four different G protein-coupled receptors, eliciting a variety of effects. We reported that activation of the EP 3 receptor reduces cardiac contractility. More recently, we have shown that overexpression of the EP 4 receptor is protective in a mouse myocardial infarction model. We hypothesize in this study that the relative abundance of EP 3 and EP 4 receptors is a major determinant of end-organ damage in the diseased heart. Thus EP 3 is detrimental to cardiac function and promotes inflammation, whereas antagonism of the EP 3 receptor is protective in an ANG II hypertension (HTN) model. To test our hypothesis, male 10- to 12-wk-old C57BL/6 mice were anesthetized with isoflurane and osmotic minipumps containing ANG II were implanted subcutaneously for 2 wk. We found that antagonism of the EP 3 receptor using L798,106 significantly attenuated the increase in blood pressure with ANG II infusion. Moreover, antagonism of the EP 3 receptor prevented a decline in cardiac function after ANG II treatment. We also found that 10- to 12-wk-old EP 3 -transgenic mice, which overexpress EP 3 in the cardiomyocytes, have worsened cardiac function. In conclusion, activation or overexpression of EP 3 exacerbates end-organ damage in ANG II HTN. In contrast, antagonism of the EP 3 receptor is beneficial and reduces cardiac dysfunction, inflammation, and HTN. NEW & NOTEWORTHY This study is the first to show that systemic treatment with an EP 3 receptor antagonist (L798,106) attenuates the angiotensin II-induced increase in blood pressure in mice. The results from this project could complement existing hypertension therapies by combining blockade of the EP 3 receptor with antihypertensive drugs.

Adropin is a recently identified bioactive protein that promotes energy homeostasis by affecting glucose and lipid metabolism. Recently, adropin has also been reported to be associated with endothelial dysfunction. Also, ET-1, as a biomarker for endothelial dysfunction, is a key regulator in hypertension. Accordingly, the aim of the present study was to detect the relationship between plasma adropin and ET-1 levels in hypertension. A total of 123 participants, diagnosed with primary hypertension on the basis of World Health Organization criteria (systolic blood pressure [SBP] ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg), and 58 normotensive subjects were enrolled in the cross-sectional study from October 2011 to December 2013. All study participants were older than 18 years of age. Adropin and ET-1 levels were measured by enzyme-linked immunosorbent assay (ELISA). We found that plasma adropin levels were significantly lower in hypertensives compared with controls (3.18 ± 1.00 vs 4.21 ± 1.14 ng/mL, P < 0.001). Plasma ET-1 levels were higher in hypertensives than controls (2.60 ± 1.14 vs 1.54 ± 0.66 pg/mL, P < 0.001). Adropin had a negative correlation with DBP (r = -0.40, P < 0.001), SBP (r = -0.49, P < 0.001), and adjusted for age, body mass index, SBP, DBP, glucose, TC, TG, LDL, and Cr, there was a negative correlation between ET-1 and adropin (r = -0.20, P = 0.04). In multivariate logistic regression analysis of the variables, ET-1 (odds ratio [OR], 3.84; 95% CI, 2.16-6.81; P < 0.001) and adropin (OR, 0.99; 95% CI, 0.99 -1.0; P <  .001) were found to be independent predictors for hypertension.In conclusion, decreased plasma adropin levels are associated with increased blood pressure in hypertension. Adropin is an independent predictor for hypertension, and may influence blood pressure by protecting endothelial function.

High blood pressure (HBP) is an important risk factor for cardiac, renal, and vascular dysfunction. Excess inflammation is the major pathogenic mechanism for HBP-induced target organ damage (TOD). N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a tetrapeptide specifically degraded by angiotensin converting enzyme (ACE), reduces inflammation, fibrosis, and TOD induced by HBP. Our hypothesis is that Ac-SDKP exerts its anti-inflammatory effects by inhibiting: 1) differentiation of bone marrow stem cells (BMSC) to macrophages, 2) activation and migration of macrophages, and 3) release of the proinflammatory cytokine TNF-alpha by activated macrophages. BMSC were freshly isolated and cultured in macrophage growth medium. Differentiation of murine BMSC to macrophages was analyzed by flow cytometry using F4/80 as a marker of macrophage maturation. Macrophage migration was measured in a modified Boyden chamber. TNF-alpha release by activated macrophages in culture was measured by ELISA. Myocardial macrophage activation in mice with ANG II-induced hypertension was studied by Western blotting of Mac-2 (galectin-3) protein. Interstitial collagen deposition was measured by picrosirius red staining. We found that Ac-SDKP (10 nM) reduced differentiation of cultured BMSC to mature macrophages by 24.5% [F4/80 positivity: 14.09 +/- 1.06 mean fluorescent intensity for vehicle and 10.63 +/- 0.35 for Ac-SDKP; P < 0.05]. Ac-SDKP also decreased galectin-3 and macrophage colony-stimulating factor-dependent macrophage migration. In addition, Ac-SDKP decreased secretion of TNF-alpha by macrophages stimulated with bacterial LPS. In mice with ANG II-induced hypertension, Ac-SDKP reduced expression of galectin-3, a protein produced by infiltrating macrophages in the myocardium, and interstitial collagen deposition. In conclusion, this study demonstrates that part of the anti-inflammatory effect of Ac-SDKP is due to its direct effect on BMSC and macrophage, inhibiting their differentiation, activation, and cytokine release. These effects explain some of the anti-inflammatory and antifibrotic properties of Ac-SDKP in hypertension.

BACKGROUND: Prostaglandin E2 acts through 4 G-protein-coupled receptors (EP1–EP4). We previously reported that activation of the EP3 receptor reduces cardiac contractility, and its expression increases after a myocardial infarction (MI), mediating the reduction in cardiac function. In contrast, cardiac overexpression of the EP4 receptor in MI substantially improves cardiac function. Moreover, we recently reported that mice overexpressing EP3 have heart failure under basal conditions and worsened cardiac function after MI. Thus, the deleterious effects of the prostaglandin E2 EP receptors in the heart are mediated via its EP3 receptor. We, therefore, hypothesized that cardiomyocyte-specific knockout (CM-EP3 KO) or antagonism of the EP3 receptor protects the heart after MI. METHODS: To test our hypothesis, we made the novel CM-EP3 KO mouse and subjected CM-EP3 KO or controls to sham or MI surgery for 2 weeks. In separate experiments, C57BL/6 mice were subjected to 2 weeks of MI and treated with either the EP3 antagonist L798 106 or vehicle starting 3 days post-MI. RESULTS: CM-EP3 KO significantly prevented a decline in cardiac function after MI compared with WT animals and prevented an increase in hypertrophy and fibrosis. Excitingly, mice treated with L798 106 3 days after MI had significantly better cardiac function compared with vehicle-treated mice. CONCLUSIONS: Altogether, these data suggest that EP3 may play a direct role in regulating cardiac function, and pharmaceutical targeting of the EP3 receptor may be a therapeutic option in the treatment of heart failure. [ABSTRACT FROM AUTHOR]

Angiotensin II (ANG II) plays a key role in regulating blood pressure and inflammation. Prostaglandin E2 (PGE2) signals through four different G protein-coupled receptors, eliciting a variety of effects. We reported that activation of the EP3 receptor reduces cardiac contractility. More recently, we have shown that overexpression of the EP4 receptor is protective in a mouse myocardial infarction model. We hypothesize in this study that the relative abundance of EP3 and EP4 receptors is a major determinant of end-organ damage in the diseased heart. Thus EP3 is detrimental to cardiac function and promotes inflammation, whereas antagonism of the EP3 receptor is protective in an ANG II hypertension (HTN) model. To test our hypothesis, male 10- to 12-wk-old C57BL/6 mice were anesthetized with isoflurane and osmotic minipumps containing ANG II were implanted subcutaneously for 2 wk. We found that antagonism of the EP3 receptor using L798,106 significantly attenuated the increase in blood pressure with ANG II infusion. Moreover, antagonism of the EP3 receptor prevented a decline in cardiac function after ANG II treatment. We also found that 10- to 12-wk-old EP3-transgenic mice, which overexpress EP3 in the cardiomyocytes, have worsened cardiac function. In conclusion, activation or overexpression of EP3 exacerbates end-organ damage in ANG II HTN. In contrast, antagonism of the EP3 receptor is beneficial and reduces cardiac dysfunction, inflammation, and HTN. [ABSTRACT FROM AUTHOR]

The natural peptide N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) decreases inflammation in chronic diseases such as hypertension and heart failure. However, Ac-SDKP effects on acute inflammatory responses during myocardial infarction (MI) are unknown. During the first 72 hours post-MI, neutrophils, M1 macrophages (pro-inflammatory), and M2 macrophages (pro-resolution) and release of myeloperoxidase (MPO) and matrix metalloproteinases (MMP) are involved in cardiac rupture. We hypothesized that in the acute stage of MI, Ac-SDKP decreases the incidence of cardiac rupture and mortality by preventing immune cell infiltration as well as by decreasing MPO and MMP expression. MI was induced by ligating the left descending coronary artery in C57BL/6 mice. Vehicle or Ac-SDKP (1.6 mg/kg/d) was infused via osmotic minipump. Cardiac immune cell infiltration was assessed by flow cytometry, cardiac MPO and MMP levels were measured at 24–48 hrs post-MI. Cardiac rupture and mortality incidence were determined at 7 days post-MI. In infarcted mice, Ac-SDKP significantly decreased cardiac rupture incidence from 51.0% (26 of 51 animals) to 27.3% (12 of 44) and mortality from 56.9% (29 of 51) to 31.8% (14 of 44). Ac-SDKP reduced M1 macrophages in cardiac tissue after MI, without affecting M2 macrophages and neutrophils. Ac-SDKP decreased MMP-9 activation in infarcted hearts with no changes on MPO expression. Ac-SDKP prevents cardiac rupture and decreases mortality post-acute MI. These protective effects of Ac-SDKP are associated with decreased pro-inflammatory M1 macrophage infiltration and MMP-9 activation. [ABSTRACT FROM AUTHOR]