Pectolinarigenin and Diosmetin Ameliorate Myocardial Ischemia–Reperfusion Injury by Activating PPARγ/GLUT4 Pathway

Background/Objectives: Myocardial ischemia–reperfusion injury (MIRI) is a common complication of thrombolysis, interventional procedures, and bypass surgery, posing a significant threat to patient outcomes. Previous evidence suggests that peroxisome proliferator-activated receptor-γ (PPARγ) agonists can upregulate cardiac glucose transporter 4 (GLUT4) expression after MIRI, thereby enhancing myocardial glucose transport and utilization to improve energy recovery and alleviate injury. This study aimed to screen natural flavonoids for PPARγ agonist activity and to evaluate the cardioprotective effects of the most potent candidates against MIRI. Methods: We assessed 44 natural flavonoids for PPARγ activation using a reporter assay. The selected compounds—diosmetin and pectolinarigenin—were then tested in an isolated perfused heart model of ischemia/reperfusion (I/R) in C57BL/6 mice, measuring infarct size, electrocardiograms, and field potentials. In H9C2 cardiomyocytes subjected to oxygen–glucose deprivation/reoxygenation (OGD/R), we evaluated the release of creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and troponin (Tn). PPARγ and GLUT4 expression were analysed by qPCR and Western blot, and molecular docking was performed to predict binding modes. Results: Both diosmetin and pectolinarigenin exhibited potent PPARγ agonist activity. In isolated hearts, treatment with either compound significantly reduced infarct size and improved electrocardiographic parameters and field potentials compared with the untreated I/R group. In OGD/R-exposed H9C2 cells, both compounds lowered CPK, LDH, and Tn levels. Diosmetin increased GLUT4 protein without significantly altering PPARγ or GLUT4 mRNA, whereas pectolinarigenin increased PPARγ, GLUT4, and total CD36 mRNA and protein in ex vivo hearts. The effects on GLUT4 and CD36 differed between ex vivo hearts and H9C2 cells. Molecular docking revealed that both compounds bind to PPARγ at the interface between helix H3 and the β-sheet. Conclusions: Diosmetin and pectolinarigenin show strong protective effects associated with PPARγ/GLUT4 pathway activation against MIRI in vitro and ex vivo, acting through enhanced GLUT4-mediated glucose metabolism. These flavonoids represent promising lead candidates for further preclinical development in MIRI management.