Molecular basis of a novel theraphy for cardioprotection through the administration of polyunsaturated fatty acids and vitamins C and E.
Keywords: omega 3, oxidative stress, cardiac ischemia, vitamin C, vitamin E
Ischemic heart disease secondary to acute myocardial infarction (AMI) is among the most prevalent health problems in the world, and is a major cause of morbidity and mortality. Two major types of myocardial injury occur following myocardial reperfusion: (1) stunning – manifested by reversible contractile dysfunction, and (2) infarction – with irreversible cell death. In addition, reperfusion is associated with potentially lethal arrhythmias that are rapidly and predictably induced within seconds of the onset of reflow. Considerable evidence attributes reactive oxygen species (ROS), produced either by the myocardium itself or by infiltrating inflammatory cells, as an early event in this process. Once produced, ROS can lead to cellular damage through a number of pathways including direct damage to membranes and proteins or indirect damage through the activation of pro-apoptotic pathways. In this view, both ischemic preconditioning and postconditioning are fascinating endogenous mechanism that when activated produce a powerful and, in some instances, prolonged cardioprotective effect to markedly reduce infarct size (IS) in a variety of animal species including humans. The cardioprotective effects of fish oil, together with specific experimental evidence of preconditioning, such as effects on heart function, suggests that omega 3 (n-3) polyunsaturated fatty acids (PUFA) provide protection that might be the nutritional equivalent of ischemic preconditioning or pharmacological preconditioning. Regular intake can slow the heart rate, reduce myocardial oxygen consumption, and increase coronary reserve. On the other hand, postconditioning mechanism of cardioprotection includes preservation of mitochondrial function, most recently the attenuation of opening of the mitochondrial permeability transition pore (MPTP). A bridge linking these mechanisms is the oxidative stress occurrence. However, conclusive studies to support the benefit of administration of antioxidants vitamins C and E during the early reperfusion are still lacking. Hypotheses. The cardioprotective effect of a diet rich in n-3 PUFA is enhanced by acute administration (during reperfusion) of the antioxidant vitamins C and E, determining a lower infarct size in rats. This finding is associated with increased antioxidant defenses and reduced oxidative damage in the myocardium. Methodology. Male Wistar rats (n=25) that weight approximately 200-300g will be supplemented to n-3 PUFA (150 mg, Acoles TG, Recalcine ®) for 8 weeks. Experiments will be performed in isolated hearts from male Wistar rats (250-350 g body wt) perfused according to the Langendorff technique in 7 groups: Group 1 (control), hearts not been perfused with KBS and used as control group. Group 2 (positive control), hearts will be subjected to global ischemia for 30 min followed by 120 min of reperfusion with KBS. The groups 3 and 4 will be used the same design that groups 1 and 2, but without pretreatment with n-3 PUFA. The remaining groups will be pre-treated with n-3 PUFA. Group 5 (reperfused + vitamin C), hearts will be perfused for 10 min with a KBS in the presence of 15 mM vitamin C. Group 6 (reperfused + vitamin E), hearts will be perfused for 10 min with a KBS solution in the presence of 6,6 mUI of a-tocopherol. Group 7 (reperfused + vitamin C + vitamin E), will be perfused for 10 min 15 mM vitamin C and 6,6 mUI of a-tocopherol. In each group will be determined infarct size, the composition of the mitochondrial membrane, parameters of oxidative stress (Glutathione content and lipidperoxidation), antioxidant enzymes activity and activation of transcriptional factor Nfr2. Perspectives. The abovementioned considerations support the hypothesis that this novel strategy could provide a safe short-term therapy designed to prevent the myocardial damage that currently occurred in patients who worldwide being subjected to primary angioplasty, Indeed, this concepts should encourage the design and execution of clinical trials aimed to protect the myocardium against the lethal reperfusion damage.
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