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  • Aconitase clusters are prone to oxidations and are among the

    2024-05-22

    Aconitase clusters are prone to oxidations and are among the first to undergo a change in transition state during stages of electrophilic stress rendering them inactive [31]. Aconitase activity in LETO and OLETF did not differ at T0 suggesting that the early onset of insulin resistance may not be attributed to robust differences in aconitase activity. However, the decreased activity in OLETF at T60 indicates that the early onset of insulin resistance is associated with impaired glucose handling and likely making the mitochondria susceptible to glucose-induced oxidation and damage. The substantial increase in aconitase activity at T0 in ARB is indicative of the protective effects of chronic AT1 blockade and of a strong association between aconitase activity and AT1 signaling. Despite the dramatic reduction in aconitase activity in ARB following the acute glucose challenge, this level remained substantially greater than those in LETO and OLETF, and was equivalent to their levels at baseline (T0) suggesting that chronic blockade of AT1 helped stabilize the response to a glucose insult. Enzymes within the raas inhibitor transport chain such as NADH dehydrogenase (complex I) and succinate dehydrogenase (complex II) are also susceptible to oxidative modification, and it has been proposed that electrons under some circumstances may flow backwards liberating a superoxide radical in the process [22,23]. Furthermore, succinate levels may increase in metabolically compromised hearts resulting from complex II no longer processing reactions in a forward direction or from oxidation [5]. Furthermore, increased succinate levels in the kidney have been attributed to increasing renin levels, which is the rate limiting enzyme in the formation of Ang II [30]. Chronic AT1 blockade helped stabilize these complex-mediated mitochondrial functions by: 1) ameliorating the susceptibility of complex I activity to an acute glucose insult, and 2) increasing complex II activity. While corresponding changes in heart succinate content and complex II activity levels did not align at the measurement time points, the increased activity in ARB at T60 was followed by substantially reduced succinate content at T120 suggesting that the effects of the changes in enzyme activity on substrate availability are not imparted for at least the following hour in vivo. This suite of mitochondrial measurements demonstrates: 1) the consequences of inappropriate AT1 activation on mitochondrial activity and succinate clearance in the early stages of insulin resistance and metabolic syndrome, and 2) the benefits of chronic AT1 blockade on ameliorating the glucose-induced impairments on mitochondrial function. SOD, CAT, and GPx are key enzymes responsible for detoxifying oxidants in the cellular environment. Manganese SOD, found in the mitochondria was decreased in OLETF rats while no differences between LETO and OLETF were observed with copper-zinc SOD in the cytosol. However, ARB treatment increased Cu/ZnSOD in the cytosol. In addition to lower expression of MnSOD, increases in mitochondrial 4HNE and NT content was also observed confirming an increase in mitochondrial damage. This suggests that the mitochondria may not be as well equipped to deal with the rapid dismutation of superoxide to hydrogen peroxide during insulin resistance. CAT and GPx are important for removing cellular H2O2, and thus, detoxifying cells with an oxidizing environment, the decreased activity levels of both in insulin resistant OLETF rats at T0 suggests that the oxidative damage associated with insulin resistance and other metabolic disorders is a consequence of an impaired ability to reduce excess free radical production. Conversely, chronic blockade of AT1 prevented the insulin resistance-associated decrease in CAT activity indicating the impact of activated AT1 signaling on catalase activity in the heart during insulin resistance. Interestingly, the greatest reduction in GPx activity was observed in ARB treated rats; however, we propose that the maintenance of catalase activity may be sufficiently efficient at removing excess H2O2 to minimize the need for elevated GPx levels. Thus, the increased catalase activity levels may compensate for the reduced GPx levels. Furthermore, glucose either suppressed or tended to suppress antioxidant enzyme activities in LETO and OLETF, but chronic blockade of AT1 consistently prevented this glucose effect highlighting the detriments of inappropriately activated AT1 on redox balance during the manifestation of insulin resistance, and ultimately, metabolic syndrome. Overall, these effects on antioxidant activities imparted by an acute glucose challenge demonstrate how insulin resistance incapacitates the heart from appropriately responding to oxidant generation caused by hyperglycemia, with the consequences being magnified by frequent bouts of exposure to acutely elevated plasma glucose as with a Western diet.