Evaluation of the synergistic effect of triple combination therapy on the myocardial function and infarction size and mitochondrial protection mechanisms following myocardial ischemia-reperfusion injury in aged rats with type-II diabetes

Abstract

The metabolic and intracellular abnormalities in aging and diabetes cause loss of cardioprotection by routine interventions against myocardial ischemia/reperfusion (I/R) injury. We aimed to evaluate the possible interaction of aging and type-2 diabetes mellitus with cardioprotection and the potential protective effect of a mitochondrial cocktail (melatonin/nicotinamide mononucleotide (NMN)/ubiquinol) on myocardial I/R injury in aged diabetic rats. Methods: Male Wistar rats (n=108, 22-24 months old, 400–450g) received high-fat diet/low dose of streptozotocin to induce type-2 diabetes, then were randomized into 9 groups of 12 rats each with/without I/R and/or melatonin, NMN, and ubiquinol, alone or in dual or triple combinations. Myocardial I/R was induced by LAD occlusion for 30 min followed by 24 hours reperfusion. NMN (100 mg/kg/48hours, intraperitoneally) was administered for 28 days before I/R operation. Melatonin (10 mg/kg, intraperitoneally) and/or ubiquinol (30 mg/kg, intravenously) were administered at early reperfusion. Finally, hemodynamic index changes, infarct size, CK-MB levels, mitochondrial functional endpoints, and expression of mitochondrial biogenesis genes (SIRT-1/PGC-1α/NRF-2/TFAM) were assessed. Results: The solo and dual applications of melatonin, NMN, and ubiquinol did not exert remarkable cardioprotective impacts. However, the triple combination improved myocardial function and decreased infarct size and CK-MB levels following myocardial I/R (P<.05 to P<.01). It also restored mitochondrial function and biogenesis genes (P<.01).