Nicotinamide mononucleotide and melatonin counteract myocardial ischemia-reperfusion injury by activating SIRT3/FOXO1 and reducing apoptosis in aged male rats.

It has been documented that aging increases the risk of cardiovascular disease including myocardial ischemia/reperfusion (IR) injury and acute myocardial infarction. In this study, we aimed to investigate the individual or combined effects of nicotinamide mononucleotide (NMN) and melatonin (Mel) treatment on apoptotic markers, expression of SIRT3, and FOXO1, and infarct size of the aged myocardium subjected to IR injury. Sixty aged Wistar rats (22-24 months) were assigned to five groups including sham, IR, NMN+IR, Mel+IR, and NMN+Mel+IR (combination therapy). Isolated hearts were exposed to 30-min regional ischemia followed by 60-min reperfusion. NMN (100 mg/kg/day/i.p.) was injected every second day starting on day 28 before IR injury. Melatonin was added to the perfusion solution five minutes prior to and until 15 min after the start of reperfusion. The infarct size was assessed by computerized planimetry. The mRNA levels of SIRT3, FOXO1, and apoptotic genes Bax, Bcl-2, and Caspase-3 were estimated by real-time PCR. All treatments reduced infarct size as compared with the IR group. Melatonin and NMN upregulated the gene expression of Bcl-2, SIRT3, and FOXO1 and downregulated the gene expression of Bax, and Caspase-3, in comparison to the IR group. Also, the protein levels of SIRT3, quantified by Western blotting, were upregulated by the interventions. The effects of combination therapy were significantly greater than those of melatonin or NMN alone. These findings indicate that the combined administration of NMN and melatonin can protect the aged heart against IR injury by decreasing apoptosis and activating the SIRT3/FOXO1 pathway.

Effect of Ischemic Postconditioning on Myocardial Function and Infarct Size Following Reperfusion Injury in Diabetic Rats Pretreated With Vildagliptin.

BACKGROUND: Cardioprotective actions of ischemic postconditioning (IPostC) against ischemia/reperfusion (I/R) injury are abolished in diabetic hearts. This study has investigated the combined effects of IPostC and vildagliptin (Vilda) on myocardial function and infarct size (IS) against I/R injury in diabetic myocardium. METHODS: Diabetes was induced by a high-fat diet/low dose of streptozotocin (35 mg/kg; intraperitoneally) in Wistar rats (200-250 g) and lasted for 12 weeks. Vilda (6 mg/kg/d) was orally administered for 5 weeks in diabetic groups after seventh week of diabetes. At the end of the 12-week period, the hearts of rats were removed and subjected to 35-minute regional ischemia (through left anterior descending ligation) followed by 60-minute reperfusion, on Langendorff apparatus. Ischemic postconditioning was induced by 6 repetitive cycles of 10-second ischemia and 10-second reperfusion, immediately at the onset of the reperfusion. Myocardial hemodynamic was measured throughout the experiment. The IS was assessed by triphenyltetrazolium chloride staining method. The myocardial contents of troponin-I (cTnI), interleukin-6 (IL-6), and 8-isoprostane were measured in the homogenate from ischemic zone of left ventricles by enzyme-linked immunosorbent assay kit. RESULTS: Pretreatment of the diabetic rats with Vilda significantly recovered the diabetes-induced reduction in left ventricular developed pressures and contractility at the baseline ( P < .05 to P < .01). After I/R injury, IPostC could not significantly improve the myocardial function, cTnI content, and IS of the diabetic hearts. However, in Vilda-treated hearts, concomitant application of IPostC significantly recovered the heart functions, returned cTnI content as well as myocardial IL-6 and 8-isoprostane levels back to the control values ( P < .01 to P < .001), and reduced IS more effectively (by 45%) in comparison to the diabetic group ( P < .001). CONCLUSION: Besides its glycemic and lipid profile controlling effects, Vilda has a protective effect on heart function and tends to restore cardioprotective effects of IPostC on diabetic hearts.

Application of ischemic postconditioning's algorithms in tissues protection: response to methodological gaps in preclinical and clinical studies.

Ischaemic postconditioning (IPostC) was introduced for the first time by Zhao et al. as a feasible method for reduction of myocardial ischaemia-reperfusion (IR) injury. The cardioprotection by this protocol has been extensively evaluated in various species. Then, further research revealed that IPostC is a safe and convenient approach in limiting IR injury of non-myocardial tissues such as lung, liver, kidney, intestine, skeletal muscle, brain and spinal cord. IPostC has been conducted with different algorithms, resulting in diverse effects. The possible important factors leading to these differences are the difference in activation levels of signalling pathways and protective mediators by any algorithm, presence or absence of IPostC effectors in each tissue, or intrinsic characteristics of the tissues as well as the methodological biases. Also, the conflicting results have been shown with the application of the same algorithm of IPostC in certain tissues or animal species. The effectiveness of IPostC may depend upon various parameters including the species and the tissues characteristics. For example, different heart rates and metabolic rates of the species and unequal amounts of perfusion and blood flow of the tissues should be considered as the important determinants of IPostC effectiveness and should be thought about in designing IPostC algorithms for future studies. Due to these discrepancies, there is still no optimal single IPostC algorithm applicable to any tissue or any species. This issue is the main topic of the present article.