Abstract
Background
Prostaglandin E2 receptor 4 (EP4) plays a crucial role in inflammatory diseases. Inflammatory cardiomyopathy often leads to refractory heart failure.
Purpose
We aimed to evaluate the role of EP4 in the development of inflammatory cardiomyopathy.
Methods
Experimental autoimmune myocarditis (EAM) was induced by immunization with cardiac myosin in balb/c mice. EP4 selective antagonist (CJ-42794, Cayman Chemical: 30 mg/kg/day), EP4 selective agonist (20 mg/kg/day), both, or vehicle alone was daily administrated after the immunization. Cardiac function and dimensions were assessed by echocardiography. Blood pressure and heart rate were assessed with tail-cuff method. Cardiac inflammation and fibrosis were immunohistologically examined. Molecular examination was performed by RT-PCR and immunoblotting.
Results
Cardiac dysfunction and dilatation were worsened on day 21 in EP4 antagonist-treated group compared with in the vehicle-treated group, accompanied by an increase in cellular infiltration area (21.7±1.9 vs. 11.0±2.7%, P=0.0367, respectively). Conversely, cardiac dysfunction and dilatation were improved in EP4 agonist-treated group compared with in the vehicle-treated group (Left ventricular fractional shortening: 69±3% vs. 40±4%, P<0.0001; Left ventricular systolic dimension: 0.7±0.1mm vs. 1.9±0.3mm, P=0.0007; respectively). These parameters did not show significant differences between both-treated group and the vehicle-treated group. The protective effect of EP4 stimulation in EAM was also kept on day 56. Moreover, cardiac fibrosis area as well as mRNA expressions of Type III collagen and brain natriuretic peptide in the bulk hearts was significantly reduced on day 56 in EP4 agonist-treated group compared with in the vehicle-treated group (12.3±2.4% vs. 24.7±3.0%, P=0.0278, respectively). Cardiac expression of phosphorylated smad 2/3 protein as well as TGF-β1 mRNA did not show significant differences between the 2 groups, while cardiac expression of RORgammat protein, the master regulator of Th17 immunity was increased in the EP4 antagonist-treated group.
Conclusions
EP4 activation negatively regulated the induction of cardiac autoimmunity, which alleviated cardiac dysfunction, dilatation, and fibrosis. EP4 may be a therapeutic target for preventing the development of inflammatory cardiomyopathy.
FUNDunding Acknowledgement
Type of funding sources: None.
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