Antioxidant Cardioprotection against Reperfusion Injury: Potential Therapeutic Roles of Resveratrol and Quercetin

Abstract

Ischemia-reperfusion myocardial damage is a paradoxical tissue injury occurring during percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) patients. Although this damage could account for up to 50% of the final infarct size, there has been no available pharmacological treatment until now. Oxidative stress contributes to the underlying production mechanism, exerting the most marked injury during the early onset of reperfusion. So far, antioxidants have been shown to protect the AMI patients undergoing PCI to mitigate these detrimental effects; however, no clinical trials to date have shown any significant infarct size reduction. Therefore, it is worthwhile to consider multitarget antioxidant therapies targeting multifactorial AMI. Indeed, this clinical setting involves injurious effects derived from oxygen deprivation, intracellular pH changes and increased concentration of cytosolic Ca²⁺ and reactive oxygen species, among others. Thus, we will review a brief overview of the pathological cascades involved in ischemia-reperfusion injury and the potential therapeutic effects based on preclinical studies involving a combination of antioxidants, with particular reference to resveratrol and quercetin, which could contribute to cardioprotection against ischemia-reperfusion injury in myocardial tissue. We will also highlight the upcoming perspectives of these antioxidants for designing future studies.

Keywords: antioxidants; cardioprotection; oxidative stress; quercetin; reperfusion injury; resveratrol.

Figure 1

Representation of mechanisms involved in Ischemia/Reperfusion damage. The increase in intracellular calcium concentration is related to the activation of xanthine oxidase, a pro-oxidant enzyme. The increase in intramitochondrial calcium and the pH increase during reperfusion lead to the opening of mPTP and the loss of mitochondrial transmembrane potential, associated with ROS production. Reactive oxygen species activate the NFκB transcription factor, promoting inflammation and neutrophil migration to the injury zone and increasing ROS production by NADPH oxidase. Another ROS source is the uncoupled eNOS. Reactive oxygen species peroxidize lipids, proteins, and DNA, triggering cell death, together with apoptosis that happens from the release of cytochrome c through mPTP and ferroptosis that occurs in the context of a decrease in GSH and GPX4 activity, with accumulation of lipid peroxidation products.

Figure 2

Schematic representation of the different cardioprotective effects of antioxidants and related molecules.

Figure 3

Trans resveratrol Structure (3,5,4′-trihydroxy-trans-stilbene).

Figure 4

Representation of resveratrol cardioprotective effect. Resveratrol activates the Nrf2 signaling pathway, increasing the expression of antioxidant enzymes. It also reduces the expression of pro-apoptotic proteins, such as caspase 3, via the PI3K/Akt pathway. Other effects are the reduction of inflammation and ferroptosis, which has been associated with reduced expression of TNFα, NfκB, TfR1, and increased activity of GPX4 after administration of resveratrol. The activation of SIRT1 is related to a decrease in intramitochondrial calcium concentration, which diminishes mitochondrial ROS production.

Figure 5

Quercetin Structure (3,30,40,5,7-pentahydroxyflavone).

Figure 6

Representation of quercetin cardioprotective effect. Quercetin acts through the inhibition of the enzymes xanthine oxidase, NADPH oxidase and the Fenton reaction, mechanisms leading to a decrease in ROS production. In addition, it acts by activating the selenoprotein TrxR2, which has a powerful antioxidant effect by inactivating ROS. All these mechanisms lead to a decrease in oxidative stress.