Protectin D1 alleviates cardiac ischemia-reperfusion injury in rats by up-regulating GPR37/JNK/PPAR-γ signaling pathway in cardiac macrophages

Abstract

Objective To investigate the mechanism by which protectin D1 (PD1) alleviates cardiac ischemia-reperfusion (IR) injury via GPR37/JNK/PPAR-γ signaling pathway. Methods Male adult SD rats (6-8 weeks old) were randomly divided into sham-operation group, IR group, IR+PD1 group, and IR+PD1+ cytochalasin B (CB) group. In the latter 3 groups, the rats were subjected to daily intraperitoneal injections of normal saline, PD1 (100 nmol/L), or PD1 and CB for consecutive 3 days before establishment of cardiac IR injury models. At 6, 24, and 48 h and at 2 weeks after the surgery, the hearts and blood samples were collected from each group, and the cardiac macrophages were isolated and cultured. The cardiac pathologies, changes in cardiac enzyme profile, cardiac fibrosis, serum inflammatory factors, phagocytic function of the cardiac macrophages, changes in the cell polarity, and the expressions of inflammatory factors and GPR37/JNK/ PPAR-γ signaling pathway in cultured cardiac macrophages were detected. Results In the rats with cardiac IR injury, PD1 treatment significantly alleviated the cardiac pathologies, lowered the expressions of the cardiac enzymes (P < 0.05), decreased the serum levels of IL-1β, TNF-α, and IL-6 while increased the serum levels of IL-10 and TGF-β (P < 0.05). In the cultured cardiac macrophages, PD1 treatment significantly enhanced their phagocytosis of the apoptotic cells (P < 0.05) and M2-type polarization (P < 0.05), decreased the expressions of IL-1β, TNF-α, IL-6, and increased the expressions of IL-10 and TGF-β (P < 0.05) and the expressions of GPR37, IRE1α, ATF6, PERK, p-JNK, and PPAR-γ (P < 0.05). Conclusion PD1 can alleviate cardiac IR injury in rats possibly by up-regulating the GPR37/JNK/PPAR-γ signaling pathway to enhance the phagocytic activity of the cardiac macrophages and the expressions of the anti-inflammatory factors.

Keywords

• protectin d1
• cardiac ischemia-reperfusion injury
• cardiac macrophages
• gpr37