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  • However T DM and associated

    2021-10-08

    However, T1DM and associated hyperglycemia can adversely affect the structure and function of the heart in several mechanisms including inhibiting the anabolic effect of insulin due to its deficiency, generation of higher levels of ROS and induction of lipid peroxidation, and subsequent activation of apoptosis and fibrosis [6]. Indeed, patients or animal models of T1DM have several cardiac structural and functional abnormalities including impaired systolic and diastolic functions, reduced heart weights, and degeneration of myocardial fibers. Additionally, in the failing heart state, they showed higher levels of circulatory cardiac markers such as CK-MB and LDH [6], [7], [46], [47], [48], [49], [50], [51], [52]. All these structural and functional changes with concomitant fasting hyperglycemia and hypoinsulinemia were readily detected in T1DM animal model of this study, thus validating our model. On the other hand, it was shown that cardiomyocytes apoptosis dominates that of necrosis during the late stage of T1DM and the progression to diabetic cardiomyopathy (85 folds vs. 4 fold, respectively) [53]. Hence, a consensus is currently established that ROS and subsequent cardiac TPPU sale apoptosis is the major player leading to the well-known above-mentioned structural and functional abnormalities seen in diabetic hearts. In this regard, it was shown that hyperglycemia can generate ROS via multiple interconnected mechanisms including depletion of enzymatic and non-enzymatic antioxidant systems (i.e. GSH), formation of advanced glycation end-products, activation of pro-oxidant enzymes such as protein kinase C and NADPH oxidase, increasing intracellular Ca2+ levels, and up-regulation of the renin-aldosterone-angiotensin system [54], [55]. Similarly, the pro-apoptotic effect of CO-HFD or LA on the heart of animals or cultured cardiomyocytes were shown to be mediated by generation of high levels of ROS and mainly, but at least, due to down-regulation and inhibition of GSH levels [28], [29], [30], [31]. Similar to these observations, the LVs of TDM1 diabetic rats or CO-HFD-fed rats had significantly low levels of GSH and higher levels of ROS. However, only diabetic LVs showed a significant increase in intracellular Ca2+ levels. These data are supported by other previous reports that have shown that hyperglycemia increases intracellular Ca2+ levels in the cardiomyocytes, in vivo and in vitro, by depressing the activity of sarcoplasmic reticulum ATPase (SERCA2a), A pump that is responsible for sequestering Ca2+and inducing diastolic relaxation [20], [21], [22]. However, our findings contradict those reported by Huang et al. [33] who showed that long-chain fatty acids including CO can increase intracellular Ca2+ in cultured cardiomyocytes isolated from pigs. This variation between the two studies could be explained by the variations in species, doses, and treatment period. Similar mirror images were also observed in the cultured cardiomyocytes grown in LG media supplied with LA or cultured in HG media. In addition, apoptosis was evident in the both in vivo and in vitro parts of this study as shown by the significant increase in protein levels of cleaved caspase-3. Associated with these change, our data confirm a partial but a small role of mitochondrial-mediated cell death in CO-HFD, LA, or hyperglycemia-induced cardiomyocytes apoptosis as indicated by the significant increase in cytoplasmic protein levels of cytochrome C and Bax. In the same line, many other authors have shown the involvement of intrinsic cell death in CO-HFD or hyperglycemia-induced cardiomyocytes apoptosis [9], [31], [56]. Interestingly, inhibiting the cardiac extrinsic cell death induced by both hyperglycemia and LA, in vitro (as discussed below), inhibited cardiomyocytes cell death by about 85%. These data suggest that mitochondrial cell death observed in the current study represents a very small ratio of about 15% of total cell death induced by these two independent apoptotic factors. Hence, we concluded that extrinsic cell death is TPPU sale prominent over the intrinsic cells in the late stage of diabetic hearts as well as in the hearts of animals after chronic feeding of CO-HFD.