Lack of microsomal prostaglandin E synthase-1 reduces cardiac function following angiotensin II infusion

Abstract

Harding P, Yang XP, He Q, LaPointe MC. Lack of microsomal prostaglandin E synthase-1 reduces cardiac function following angiotensin II infusion. Am J Physiol Heart Circ Physiol 300: H1053-H1061, 2011. First published December 30, 2010 doi:10.1152/ajpheart.00772.2010.-Our laboratory previously reported that inducible PGE2 synthase, mPGES-1, contributes to micromolar production of PGE2 in neonatal ventricular myocytes in vitro, which stimulates their growth. We therefore hypothesized that mPGES-1 contributes to cardiac hypertrophy following angiotensin II (ANG II) infusion. To test this hypothesis, we used 10-to 12-wk-old mPGES-1 knockout mice (mPGES-1 KO) and C57Bl/6 control mice infused for 8 wk with either 1.4 mg·kg Ϫ1 ·day Ϫ1ANG II or vehicle subcutaneously. Blood pressure [systolic blood pressure (SBP)] was measured throughout the study, and cardiac function was assessed by M-mode echocardiography at baseline and at 8 wk of infusion. At the conclusion of the study, immunohistochemistry was used to evaluate collagen fraction, myocyte crosssectional area (MCSA), and apoptosis. At baseline, there was no difference in SBP between mPGES-1 KO mice and C57BL/6 controls. ANG II infusion increased SBP to similar levels in both strains. In control mice, infusion of ANG II increased MCSA and posterior wall thickness at diastole (PWTd) but had little effect on cardiac function, consistent with compensatory hypertrophy. In contrast, cardiac function was worse in mPGES-1 KO mice after ANG II treatment. Ejection fraction declined from 76.2 Ϯ 2.7 to 63.3 Ϯ 3.4% after ANG II, and left ventricular dimension at systole and diastole increased from 1.29 Ϯ 0.02 to 1.78 Ϯ 0.15 mm and from 2.57 Ϯ 0.03 to 2.90 Ϯ 0.13 mm, respectively. Infusion of ANG II increased both the LV-to-body weight and the mass-to-body weight ratios to a similar extent in both strains. However, PWTd increased by a lesser extent in KO mice, suggesting an impaired hypertrophic response. ANG II infusion increased collagen staining similarly in both strains, but TdT-dUTP nick end labeling staining was greater in mPGES-1 KO mice. Overall, these results are consistent with a beneficial effect for mPGES-1 in the maintenance of cardiac function in ANG II-dependent hypertension.microsomal prostaglandin E synthase-1; angiotensin II; hypertrophy THE ENZYME PROSTAGLANDIN E synthase exists in three isoforms, a cytosolic form (cPGES) and two microsomal forms (mPGES-1 and mPGES-2), that are membrane attached. In contrast to mPGES-1, mPGES-2 is not activated by proinflammatory factors and is believed to play a constitutive role in PGE 2 formation. Our laboratory has previously demonstrated the existence of mPGES-1 in cardiac myocytes and fibroblasts after stimulation with interleukin-1␤, and this appears to be colocalized with cyclooxygenase (COX)-2 in a perinuclear manner (6).A number of studies demonstrate the induction of mPGES-1 coupled with increased PGE 2 production in rodent models of myocardial infarction (MI). A report from our laboratory (18) indicated that treatm...

A novel heart failure mice model of hypertensive heart disease by angiotensin II infusion, nephrectomy, and salt loading

“…Previous studies have shown that C57BL/6 mice infused with ANG II show either normal (10,12,49) or only minimal impairment in LV systolic function (53) and do not demonstrate HF. In the present study, by adding both high salt intake and unilateral nephrectomy to ANG II infusion, cardiac function of ANS mice was significantly impaired, and mice devel- Results are means Ϯ SD.…”

“…The C57BL/6 mouse strain serves as the genetic background of many transgenic and gene knockout models to validate the function of specific genes. Previous studies (10,12,49) have shown that ANG II infusion mouse models develop HHD with cardiac hypertrophy and fibrosis, but C57BL/6 mice infused with high doses of ANG II maintain cardiac function and do not develop HF (10,12,49). The transverse aortic constriction (TAC) model has been used for a mouse model of pressure overload (26), but it does not entirely mimic human HHD, and it is also difficult to prepare the model because microsurgical skills are required.…”

Distinct Roles of Central and Peripheral Prostaglandin E2 and EP Subtypes in Blood Pressure Regulation

“…7 However, another study using the same C57 background observes no impact of mPGES-1 deletion on the blood pressure (BP) response. 10 Facemire et al generated mPGES-1 −/− mice on two inbred backgrounds, DBA/1lacJ and 129/SvEv. 11 On the 129 background, BP was significantly higher in mPGES-1 −/− mice than wild type controls at baseline and also during Ang II infusion.…”

Cardiovascular Biology of Microsomal Prostaglandin E Synthase-1

“…We and others have reported that deletion of mPGES-1fails to elevate blood pressure in mice fed either a normal or high salt diet (Cheng et al 2006; Francois et al 2007). Hypertension induced by infusion of angiotensin II in hyperlipidemic mice is also uninfluenced by mPGES-1 deletion(Harding et al 2011; Wang et al 2008). In contrast to these observations, Jia et al reported that mPGES-1 deletion augmented the hypertensive response to both a more intensive salt loading regimen and to angiotensin II infusion in normolipidemic mice (Jia et al 2006).…”

“…This adverse LV remodeling contrasts with the favorable PGI 2 dependent vascular remodeling in mPGES-1 knockout mice and is due to suppression of PGE 2 formation by inflammatory cells in the infarct and peri-infarct regions(Degousee et al 2008). Others reported that depletion of mPGES-1 impairs the compensatory hypertrophic response to prolonged angiotensin II infusion and reduces the ejection fraction (Harding et al 2011). These studies raise the possibility of adverse cardiac effects of mPGES-1 inhibitors in patients who had recently suffered a myocardial infarction or exhibit cardiac decompensation.…”