Cardioprotection against ischaemia/reperfusion by vitamins C and E plus n−3 fatty acids: molecular mechanisms and potential clinical applications

Abstract

The role of oxidative stress in ischaemic heart disease has been thoroughly investigated in humans. Increased levels of ROS (reactive oxygen species) and RNS (reactive nitrogen species) have been demonstrated during ischaemia and post-ischaemic reperfusion in humans. Depending on their concentrations, these reactive species can act either as benevolent molecules that promote cell survival (at low-to-moderate concentrations) or can induce irreversible cellular damage and death (at high concentrations). Although high ROS levels can induce NF-κB (nuclear factor κB) activation, inflammation, apoptosis or necrosis, low-to-moderate levels can enhance the antioxidant response, via Nrf2 (nuclear factor-erythroid 2-related factor 2) activation. However, a clear definition of these concentration thresholds remains to be established. Although a number of experimental studies have demonstrated that oxidative stress plays a major role in heart ischaemia/reperfusion pathophysiology, controlled clinical trials have failed to prove the efficacy of antioxidants in acute or long-term treatments of ischaemic heart disease. Oral doses of vitamin C are not sufficient to promote ROS scavenging and only down-regulate their production via NADPH oxidase, a biological effect shared by vitamin E to abrogate oxidative stress. However, infusion of vitamin C at doses high enough to achieve plasma levels of 10 mmol/l should prevent superoxide production and the pathophysiological cascade of deleterious heart effects. In turn, n-3 PUFA (polyunsaturated fatty acid) exposure leads to enhanced activity of antioxidant enzymes. In the present review, we present evidence to support the molecular basis for a novel pharmacological strategy using these antioxidant vitamins plus n-3 PUFAs for cardioprotection in clinical settings, such as post-operative atrial fibrillation, percutaneous coronary intervention following acute myocardial infarction and other events that are associated with ischaemia/reperfusion.

The endothelial nitric oxide synthase cofactor tetrahydrobiopterin shields the remote myocardium from apoptosis after experimental myocardial infarction in vivo

“…In addition, stabiliser-only pretreated animals also showed blunted caspase 8 and 3 activation and reduced pro-apoptotic activity via the intrinsic pathway, again resembling the effects of BH4 pretreatment. Anti-apoptotic properties of ascorbic acid have previously been demonstrated for the prevention of FAS-ligand-induced apoptosis via the extrinsic pathway and reduction of nitrosative stress due to inhibition of NADPH-oxidase [23]. This might explain the observed cardioprotective properties of the stabiliser formation in our study.…”

Effects of a novel ascorbate-based protocol on infarct size and ventricle function in acute myocardial infarction patients undergoing percutaneous coronary angioplasty

“…Taking into account that ROS produces rapid and irreversible damage to myocardial tissue and other organs, it is plausible that antioxidants may counteract this damage [11–15]. Numerous attempts using pharmacological strategies have targeted oxidative stress to prevent this phenomenon, but none of them have succeeded, probably due to a lack of consideration of the basic pharmacokinetic and pharmacodynamic aspects of antioxidants [5].…”

“…Numerous attempts using pharmacological strategies have targeted oxidative stress to prevent this phenomenon, but none of them have succeeded, probably due to a lack of consideration of the basic pharmacokinetic and pharmacodynamic aspects of antioxidants [5]. Ascorbate has been one of the most widely used antioxidants for this purpose due to its ability to directly reduce ROS [11]. In addition to its ROS scavenger actions, it exerts a complex modulation of numerous enzymes involved in ROS production, endothelial dysfunction, platelet aggregation and smooth muscle cell tone [16].…”

Non-targeted metabolomics analysis of cardiac Muscle Ring Finger-1 (MuRF1), MuRF2, and MuRF3 in vivo reveals novel and redundant metabolic changes

“…In the case of taurine, evidence for its role in cardiac physiology is exemplified by its development as a therapy for heart disease in Japan (Ito, Schaffer, Azuma 2014). Similarly, the role of MuRF1 and MuRF2 on fatty acid synthesis and ascorbic acid/aldarate metabolism is provocative given the primary role of fatty acids in cardiomyocyte energy production (Lopaschuk, Ussher, Folmes, Jaswal, Stanley 2010) and the production of antioxidants critical to the hearts resistance to ischemia (Rodrigo, Prieto, Castillo 2013), respectively. These novel metabolomics findings will aid in guiding the molecular studies delineating the mechanisms that MuRF family proteins regulate metabolic pathways.…”