Prostaglandin-E2 receptor-4 stimulant rescues cardiac malfunction during myocarditis and protects the heart from adverse ventricular remodeling after myocarditis

Abstract

Cardioprotective effect of prostaglandin-E2 receptor-4 (EP4) stimulation on the ischemic heart has been demonstrated. Its effect on the heart affected by myocarditis, however, remains uncertain. In this study, we investigated therapeutic effect of EP4 stimulant using a mouse model of autoimmune myocarditis (EAM) that progresses to dilated cardiomyopathy (DCM). EP4 was present in the hearts of EAM mice. Treatment with EP4 agonist (ONO-0260164: 20 mg/kg/day) improved an impaired left ventricular (LV) contractility and reduction of blood pressure on day 21, a peak myocardial inflammation. Alternatively, DCM phenotype, characterized by LV dilation, LV systolic dysfunction, and collagen deposition, was observed on day 56, along with activation of matrix metalloproteinase (MMP)-2 critical for myocardial extracellular matrix disruption, indicating an important molecular mechanism underlying adverse ventricular remodeling after myocarditis. Continued treatment with ONO-0260164 alleviated the DCM phenotype, but this effect was counteracted by its combination with a EP4 antagonist. Moreover, ONO-0260164 inhibited in vivo proteolytic activity of MMP-2 in association with up-regulation of tissue inhibitor of metalloproteinase (TIMP)-3. EP4 stimulant may be a promising and novel therapeutic agent that rescues cardiac malfunction during myocarditis and prevents adverse ventricular remodeling after myocarditis by promoting the TIMP-3/MMP-2 axis.

Prostaglandin E2 mediates the late phase of ischemic preconditioning in the heart via its receptor subtype EP4

“…This suggests that Akt signaling underlies the cardioprotective mechanism of the PGE 2 /EP 4 system in I/R. Additionally, several studies demonstrated the utility of EP 4 as a promising therapeutic target in cardiac diseases including not only ischemic heart disease but also inflammatory heart disease [ 34 ] and cardiac hypertrophy [ 35 ]. Further investigations are necessary to extend the clinical benefits of EP 4 agonists in cardiac disease.…”

Prostanoids in Cardiac and Vascular Remodeling

“…158 An EPr4 agonist reduces myocardial fibrosis in response to pressure overload 159 and reduces myocardial fibrosis, hypertrophy, and inflammation after myocarditis. 160,161 PGE 2 also regulates cardiac contractility: it reduces cardiac contractility via the EPr3 receptor 162 and increases it via the EPr4 receptor. 162 PGE 2 may also play a role in cardiac regeneration.…”

“…158 An EPr4 agonist reduces myocardial fibrosis in response to pressure overload 159 and reduces myocardial fibrosis, hypertrophy, and inflammation after myocarditis. 160,161…”

Stable Gastric Pentadecapeptide BPC 157 and Striated, Smooth, and Heart Muscle

“…Furthermore, the beneficial effects ascribed to the BPC 157’s muscle healing and muscle function recovery, might have a very wide range (for review, see [ 1 , 3 , 4 , 5 , 6 , 8 , 9 , 32 , 33 , 34 , 92 ]). In its full extent, the range of BPC 157 therapy and its huge curing potential as a “treatment” (for review, see [ 1 , 3 , 4 , 5 , 6 , 8 , 9 , 32 , 33 , 34 , 92 ]) might largely override the range of the beneficial effects commonly reported with standard cytoprotective agents (for review, see [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]) (i.e., prostaglandins’ beneficial effects on the stomach [ 35 ], intestine [ 38 ], liver [ 130 ], pancreas [ 39 ], kidney [ 38 , 131 ], and heart [ 132 ]). Likewise, its easy applicability during the course of an injury’s treatment might bypass the limitation of the standard agents (for review, see [ 1 , 3 , 4 , 5 , 6 , 8 , 9 , 32 , 33 ,…”