The impaired myocardial ischemic tolerance in adult offspring of diabetic pregnancy is restored by maternal melatonin treatment

Abstract

Diabetic pregnancy, with ever increasing prevalence, adversely affects embryogenesis and increases vasculometabolic disorder risks in adult offspring. However, it remains poorly understood whether maternal diabetes increases the offspring's susceptibility to heart injuries in adulthood. In this study, we observed that cardiac function and structure were comparable between adult offspring born to diabetic mice and their counterparts born to nondiabetic mice at baseline. However, in response to myocardial ischemia/reperfusion (MIR), diabetic mother offspring exhibited augmented infarct size, cardiac dysfunction, and myocardial apoptosis compared with control, in association with exaggerated activation of mitochondria- and endoplasmic reticulum (ER) stress-mediated apoptosis pathways and oxidative stress. Molecular analysis showed that the impaired myocardial ischemic tolerance in diabetic mother offspring was mainly attributable to blunted cardiac insulin receptor substrate (IRS)-1/Akt signaling. Furthermore, the effect of maternal melatonin administration on offspring's response to MIR was determined, and the results indicated that melatonin treatment in diabetic dams during pregnancy significantly improved the tolerance to MIR injury in their offspring, via restoring cardiac IRS-1/Akt signaling. Taken together, these data suggest that maternal diabetes predisposes offspring to augmented MIR injury in adulthood, and maternal melatonin supplementation during diabetic pregnancy may hold promise for improving myocardial ischemic tolerance in the offspring.

Interplay between Oxidative Stress and Nutrient Sensing Signaling in the Developmental Origins of Cardiovascular Disease

“…Since cardiovascular phenotypes often develop after a prolonged asymptomatic phase in childhood and for the sake of brevity, we have restricted this review to data obtained from adult offspring. Here we summarize in Table 1 studies documenting cardiovascular programming related to oxidative stress [43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68]. …”

“…A number of early-life insults have been reported to cause cardiovascular programming related to oxidative stress, including undernutrition [43,48,51,54,55,61,63,64], streptozotocin (STZ)-induced diabetes [44,62], preeclampsia [45,46,47], prenatal hypoxia [49,56], maternal nicotine exposure [59,60], ethanol consumption [50], maternal inflammation [57], prenatal glucocorticoid exposure [52,53,65,67,68], and maternal high-fat intake [58,66]. Limited information is available using large animals to study oxidative stress and cardiovascular programming simultaneously [67,68].…”

Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

“…For example, obesity and hyperglycaemia arise prior to maturation in db / db mice, with hyperinsulinaemia and abnormalities in myocardial metabolism, and efficiency emerging even earlier (Buchanan et al., ). Another potential drawback is intrauterine programming of stress phenotype, with maternal hyperglycaemia inducing myocardial inflammation and oxidative stress in early neonates (Higa et al., ) and I–R intolerance in adult offspring (Gao et al., ). Early disease onset and possible maternal influences may thus limit the utility of such models in delineating effects of adult disease on myocardial stress resistance: T2D predominantly emerges from early adulthood on (with 4–6 years from metabolic dysfunction to T2D diagnosis) (Porta et al., ), and late onset or latent autoimmune diabetes of the adult is even more prevalent than childhood T1D (Laugesen, Ostergaard, Leslie, & Danish Diabetes Academy Workshop and Workshop Speakers, ).…”

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

“…The chemical structure of melatonin has remained very stable for billions of years, and its structure is identical from cyanobacteria to human beings 25, 26, 27. In recent years, a vast number of studies have documented the involvement of melatonin in cardiac protection 28, 29, 30, 31, 32, 33. Melatonin presumably enters mitochondria through oligopeptide transporters 34.…”