RESUMO
BACKGROUND: Myocardial infarction (MI) is a significant cause of death in diabetic patients. Growing evidence suggests that mitochondrial dysfunction contributes to heart failure in diabetes. However, the molecular mechanisms of mitochondrial dysfunction mediating heart failure in diabetes are still poorly understood. METHODS: The current study aimed to investigate the role of mitochondrial ribosomal protein L7/L12 (MRPL12) in human heart. Mitochondrial oxygen consumption rate and membrane potential was determined using Seahorse analysis and confocal microscopy respectively. Data was analyzed by using the mean of the groups was compared using a student t-test (for 2 groups) and ANOVA, followed by a Tukey test (for >2 groups). RESULTS: We found increased MRPL12 levels in heart tissue samples of diabetic patients with ischemic heart disease compared to non-diabetic patients. With the overexpression of MRPL12 under hyperglycemic conditions, the level of oxidative phosphorylation (OXPHOS) was found downregulated, but cellular ATP and human cardiomyocyte cell death remained unchanged, However, there was notable impairment in mitochondrial membrane potential (MMP) in hyperglycemia condition, along with changes in basal respiration oxygen consumption rate (OCR) and maximal respiratory capacity OCR. CONCLUSIONS: Overall, our results suggest that MRPL12 may have a compensatory role in the diabetic myocardium with ischemic heart disease, suggesting that MRPL12 may implicate in the pathophysiology of MI in diabetes.
RESUMO
BACKGROUND: Prenatal alcohol exposure (PAE) is associated with an increased incidence of congenital heart defects (CHD), in particular outflow tract (OFT) defects. However, the variability in the incidence of CHD following PAE has not been fully explored. We hypothesize that a concomitant, relevant genetic defect would potentiate the adverse effect of PAE and partially explain the variability of PAE-induced CHD incidence. METHODS: The OFT is formed by the second heart field (SHF). Our PAE model consisted of two intraperitoneal injections (3 g/kg, separated by 6 hr) of 30% ethanol on E6.5 during SHF specification. The impact of genetic defects was studied by SHF-specific loss of Delta-like ligand 4 (Dll4), fibroblast growth factor 8 (Fgf8) and Islet1. RESULTS: Acute PAE alone significantly increased CHD incidence (4% vs. 26%, p = .015) with a particular increase in OFT alignment defects, viz., double outlet right ventricle (0 vs. 9%, p = .02). In embryos with a SHF genetic defect, acute PAE significantly increased CHD incidence (14 vs. 63%, p < .001), including double outlet right ventricle (6 vs. 50%, p < .001) compared to controls. PAE (p = .01) and heterozygous loss of Dll4 (p = .04) were found to independently contribute to CHD incidence, while neither Islet1 nor Fgf8 defects were found to be significant. CONCLUSIONS: Our model recapitulates the increased incidence of OFT alignment defects seen in the clinic due to PAE. The presence of a concomitant SHF genetic mutation increases the incidence of PAE-related OFT defects. An apparent synergistic interaction between PAE and the loss of DLL4-mediated Notch signaling in OFT alignment requires further analysis.
