Microsomal Prostaglandin E₂ Synthase-1 Deletion Attenuates Isoproterenol-Induced Myocardial Fibrosis in Mice

Abstract

Deletion of microsomal PGE2 synthase-1 (mPGES-1) inhibits inflammation and protects against atherosclerotic vascular diseases, but displayed variable influence on pathological cardiac remodeling. Overactivation of β-adrenergic receptors (β-ARs) causes heart dysfunction and cardiac remodeling, while the role of mPGES-1 in β-ARs induced cardiac remodeling is unknown. Here we addressed this question using mPGES-1 knockout mice, and subjecting them to isoproterenol, a synthetic nonselective agonist for β-ARs, at 5mg/kg/day or 15mg/kg/day to induce different degrees of cardiac remodeling in vivo. Cardiac structure and function were assessed by echocardiography 24 hours after the last of seven consecutive daily injections of isoproterenol, and cardiac fibrosis was examined by Masson trichrome stain in morphology and by real-time PCR for the expression of fibrosis related genes. The results showed that deletion of mPGES-1 had no significant effect on isoproterenol-induced cardiac dysfunction or hypertrophy. However, the cardiac fibrosis was dramatically attenuated in the mPGES-1 knockout mice after either low dose or high dose isoproterenol exposure. Furthermore, in vitro study revealed that overexpression of mPGES-1 in cultured cardiac fibroblasts increased isoproterenol induced fibrosis, while knocking-down mPGES-1 in cardiac myocytes decreased the fibrogenesis of fibroblasts. In conclusion, mPGES-1 deletion protects against isoproterenol-induced cardiac fibrosis in mice, and targeting mPGES-1 may represent a novel strategy to attenuate pathological cardiac fibrosis, induced by β-ARs agonists.

Microsomal prostaglandin E synthase‐1 inhibition prevents adverse cardiac remodelling after myocardial infarction in mice

“…In the late phase of ventricular remodelling after MI, we found, using echocardiography and histological analyses, that the LV anterior wall thickness was significantly increased in mice given daily doses of CIII (Figures 2e,f and 3b), which was accompanied by reduction of cardiomyocyte loss and fibrosis (Figure 3c), resembling a stable tissue healing and scar formation, avoiding cardiac rupture. This is consistent with previous reports describing that mPGES‐1 deletion attenuated cardiac fibrosis in mice (Ji et al, 2020) and PGI 2 protected against fibrosis in murine models of cardiac fibrosis (Francois et al, 2005; Gomez‐Arroyo et al, 2015). The ratio of collagen I/III is associated with dilated cardiomyopathy (Marijianowski et al, 1995).…”

“…In the late phase of ventricular which was accompanied by reduction of cardiomyocyte loss and fibrosis (Figure 3c), resembling a stable tissue healing and scar formation, avoiding cardiac rupture. This is consistent with previous reports describing that mPGES-1 deletion attenuated cardiac fibrosis in mice (Ji et al, 2020) and PGI 2 protected against fibrosis in murine models of cardiac fibrosis (Francois et al, 2005;Gomez-Arroyo et al, 2015).…”

Microsomal prostaglandin E synthase‐1 is involved in the metabolic and cardiovascular alterations associated with obesity

“…The effects of mPGES‐1 deletion in cardiac damage have provided controversial results depending on the experimental model. In mice, the lack of mPGES‐1 prevents the acute post‐myocardial infarction death (Wu et al, 2009) or fibrosis induced by agonists of β‐ adrenoceptors (Ji et al, 2020). However, mPGES‐1 deletion impairs left ventricular contractile function after acute myocardial infarction (Degousee et al, 2008) or after chronic angiotensin II infusion (Harding et al, 2011) and impairs cardiac microvascular perfusion in a myocardial ischaemia reperfusion model (Zhu et al, 2019).…”

Noradrenergic Signaling in Astrocytes Influences Mammalian Sleep Homeostasis

“…Next, baseline image capture occurred for 5 min. Mice were then injected intraperitoneally with 5 mg/kg of the β-AR agonist (-)-isoproterenol hydrochloride (#I6504, Sigma-Aldrich) made in saline [ 67 , 68 ]. Image capture occurred 20 min post-injection for 2 min.…”