Quercetin Prevents Diastolic Dysfunction Induced by a High‐Cholesterol Diet: Role of Oxidative Stress and Bioenergetics in Hyperglycemic Rats

Abstract

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

Circulating levels of mitochondrial uncoupling protein 2, but not prohibitin, are lower in humans with type 2 diabetes and correlate with brachial artery flow-mediated dilation

“…In T2DM patients, we also identified circulating UCP2 levels negatively correlating with total cholesterol levels positively correlated with BMI and negatively correlated with in univariate analyses. The cholesterol finding is consistent with animal data showing suppression of UCP2 expression with a high-cholesterol diet [43]. This positive correlation with BMI differs from prior data suggesting UCP2 gene expression in adipose tissue increases with weight loss and that genetic polymorphisms that reduce tissue-level UCP2 expression area associated with increased BMI [44, 45].…”

Uncoupling Protein 2 in Cardiovascular Health and Disease

“…The cardioprotective effect of SIRT1 is also mediated by UCP2 in IR injury ( Deng et al, 2017 ). UCP2 is often used recently as a protective marker for oxidative stress and mitochondrial injury in animal models of cardiac injury or ischemic insults ( Castillo et al, 2018 ; Quan et al, 2018 ; Wang et al, 2018 ) ( Table 2 ). Based on these evidences, the upregulation of UCP2 is a response triggered by the change of redox status induced by hypoxia or during early phase after hypoxia a feedback protective mechanism to restore the balance.…”

Potential Implications of Quercetin and its Derivatives in Cardioprotection

“…In addition to its vascular effects, QCT has been shown to exert robust heart-protective effects in different kinds of cardiac injury, including ischemia-reperfusion (I/R) injury, doxorubicin-induced cardiotoxicity, diabetic cardiomyopathy and others [13][14][15][16][17]. Cardioprotective effects of QCT are associated with affecting many different signaling pathways and proteins, including inhibition of apoptosis and decreasing oxidative stress, as well as affecting inflammatory proteins in the heart [14][15][16]18].…”