Melatonin and Nicotinamide Mononucleotide Attenuate Myocardial Ischemia/Reperfusion Injury via Modulation of Mitochondrial Function and Hemodynamic Parameters in Aged Rats

Abstract

Ischemic heart diseases are the major reasons for disability and mortality in elderly individuals. In this study, we tried to examine the combined effects of nicotinamide mononucleotide (NMN) preconditioning and melatonin postconditioning on cardioprotection and mitochondrial function in ischemia/reperfusion (I/R) injury of aged male rats. Sixty aged Wistar rats were randomly allocated to 5 groups, including sham, control, NMN-receiving, melatonin-receiving, and combined therapy (NMN+melatonin). Isolated hearts were mounted on Langendorff apparatus and then underwent 30-minue ligation of left anterior descending coronary artery to induce regional ischemic insult, followed by 60 minutes of reperfusion. Nicotinamide mononucleotide (100 mg/kg/d intraperitoneally) was administered for every other day for 28 days before I/R. Melatonin added to perfusion solution, 5 minutes prior to the reperfusion up to 15 minutes early reperfusion. Myocardial hemodynamic and infarct size (IS) were measured, and the left ventricles samples were obtained to evaluate cardiac mitochondrial function and oxidative stress markers. Melatonin postconditioning and NMN had significant cardioprotective effects in aged rats; they could improve hemodynamic parameters and reduce IS and lactate dehydrogenase release compared to those of control group. Moreover, pretreatment with NMN increased the cardioprotection by melatonin. All treatments reduced oxidative stress and mitochondrial reactive oxygen species (ROS) levels and improved mitochondrial membrane potential and restored NAD+/NADH ratio. The effects of combined therapy on reduction of mitochondrial ROS and oxidative status and improvement of mitochondrial membrane potential were greater than those of alone treatments. Combination of melatonin and NMN can be a promising strategy to attenuate myocardial I/R damages in aged hearts. Restoration of mitochondrial function may substantially contribute to this cardioprotection.

Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism

“…In addition, NMN activates autophagy during myocardial ischemia, which is consistent with the finding that NAMPT and SIRT1 promote autophagy in cardiomyocytes (Hsu et al, 2009). An ex vivo experiment showed that NMN attenuated myocardial I/R injury in aged rats (Hosseini et al, 2019b). Rats treated with NMN showed improved myocardial function and reduced infarct size.…”

Role of NAD+—Modulated Mitochondrial Free Radical Generation in Mechanisms of Acute Brain Injury

“…When animals were treated with NAD + precursor NMN, the excessive mitochondrial fragmentation was prevented in cells within all hippocampal subregions [ 56 ], and there was dramatic neuroprotection observed in mice [ 65 ]. Furthermore, NMN administration also reduced ROS accumulation in genetic mouse models of heart failure [ 93 ] and myocardial ischemia/reperfusion injury [ 94 ], following hypoglycemia-induced brain damage [ 95 ], and in a brain focal ischemia model [ 96 ].…”

Effects of hyperoxia and cardiovascular risk factors on myocardial ischaemia–reperfusion injury: a randomized, sham‐controlled parallel study

“…Past experimental studies on myocardial reperfusion injury were mainly performed on young and healthy animals. However, ageing is associated with increased susceptibility to myocardial ischaemia, increased rates of mitochondrial free radical production and elevated mitochondrial DNA mutations (Hosseini et al, 2020;Lucas & Szweda, 1998). Hypertension is associated with decreased antioxidant capacity due to decreased superoxide dismutase and GPx activities in newly diagnosed patients (Pedro-Botet et al, 2000).…”