Alterations in cardiac energy metabolism play a key role in the pathogenesis of diabetic cardiomyopathy. Hypercholesterolemia\nassociated with bioenergetic impairment and oxidative stress has not been well characterized in the cardiac function under\nglycemic control deficiency conditions. This work aimed to determine the cardioprotective effects of quercetin (QUE) against\nthe damage induced by a high-cholesterol (HC) diet in hyperglycemic rats, addressing intracellular antioxidant mechanisms and\nbioenergetics. Quercetin reduced HC-induced alterations in the lipid profile and glycemia in rats. In addition, QUE attenuated\ncardiac diastolic dysfunction (increased E:A ratio), prevented cardiac cholesterol accumulation, and reduced the increase in\nHC-induced myocyte density. Moreover, QUE reduced HC-induced oxidative stress by preventing the decrease in GSH/GSSG\nratio, Nrf2 nuclear translocation, HO-1 expression, and antioxidant enzymatic activity. Quercetin also counteracted HCinduced\nbioenergetic impairment, preventing a reduction in ATP levels and alterations in PGC-1�±, UCP2, and PPAR�³\nexpression. In conclusion, the mechanisms that support the cardioprotective effect of QUE in rats with HC might be mediated\nby the upregulation of antioxidant mechanisms and improved bioenergetics on the heart. Targeting bioenergetics with QUE can\nbe used as a pharmacological approach to modulate structural and functional changes of the heart under hypercholesterolemic\nand hyperglycemic conditions.
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