Our results indicate that at lower dose, resveratrol-mediated cell survival is, in part, mediated through the induction of autophagy involving the mTOR-Rictor survival pathway.

Reactive oxygen species (ROS) are the key mediators of pathogenesis in cardiovascular diseases. Members of the thioredoxin superfamily take an active part in scavenging reactive oxygen species, thus playing an essential role in maintaining the intracellular redox status. The alteration in the expression levels of thioredoxin family members and related molecules constitute effective biomarkers in various diseases, including cardiovascular complications that involve oxidative stress. Thioredoxin, glutaredoxin, peroxiredoxin, and glutathione peroxidase, along with their isoforms, are involved in interaction with the members of metabolic and signaling pathways, thus making them attractive targets for clinical intervention. Studies with cells and transgenic animals have supported this notion and raised the hope for possible gene therapy as modern genetic medicine. Of all the molecules, thioredoxins, glutaredoxins, and peroxiredoxins are emphasized, because a growing body of evidence reveals their essential and regulatory role in several steps of redox regulation. In this review, we discuss some pertinent observations regarding their distribution, structure, functions, and interactions with the several survival-and death-signaling pathways, especially in the myocardium. Antioxid. Redox Signal. 11, 2741-2758.

This study compared two dietary phytochemicals, grape-derived resveratrol and palm oil-derived γ-tocotrienol, either alone or in combination, on the contribution of autophagy in cardioprotection during ischaemia and reperfusion. Sprague-Dawley rats weighing between 250 and 300 g were randomly assigned to one of the following groups: vehicle, ischaemia/reperfusion (I/R), resveratrol + I/R, γ-tocotrienol + I/R, resveratrol +γ-tocotrienol + I/R. For resveratrol treatments, the rats were gavaged with resveratrol (2.5 mg/kg) for 15 days while for γ-tocotrienol experiments the rats were gavaged with γ-tocotrienol (0.3 mg/kg) for 30 days. For the combined resveratrol +γ-tocotrienol experiments, the rats were gavaged with γ-tocotrienol for 15 days, and then gavaging continued with resveratrol along with γ-tocotrienol for a further period of 15 days. After 30 days, isolated perfused hearts were subjected to 30 min. of global ischaemia followed by 2 hrs of reperfusion. Our results showed for the first time that at least in part, the cardioprotection (evidenced from the ventricular performance, myocardial infarct size and cardiomyocyte apoptosis) with resveratrol and γ-toctrienol was achieved by their abilities to induce autophagy. Most importantly, resveratrol and γ-tocotrienol acted synergistically providing greater degree of cardioprotection simultaneously generating greater amount of survival signal through the activation of Akt-Bcl-2 survival pathway. Autophagy was accompanied by the activation of Beclin and LC3-II as well as mTOR signalling, which were inhibited by either 3-methyl adenine (3-MA) or Wortmannin. The autophagy was confirmed from the results of transmission electron microscopy and light microscopy as well as with confocal microscopy. It is tempting to speculate that during ischaemia and reperfusion autophagy along with enhanced survival signals helps to recover the cells from injury.

Background-Cardiac myosin-induced myocarditis is an experimental autoimmune myocarditis (EAM) model used to investigate autoimmunological mechanisms in inflammatory heart diseases and resembles fulminant myocarditis in humans. We investigated the therapeutic role of thioredoxin-1 (TRX-1), a redox-regulatory protein with antioxidant and antiinflammatory effects, in murine EAM. Methods and Results-EAM was generated in 5-week-old male BALB/c mice by immunization with porcine cardiac myosin at days 0 and 7. Recombinant human TRX-1 (rhTRX-1), C32S/C35S mutant rhTRX-1, or saline was administered intraperitoneally every second day from day 0 to 20. In addition, rabbit anti-mouse TRX-1 serum or normal rabbit serum was administered intraperitoneally on days Ϫ1, 2, and 6. Animals were euthanized on day 21. Histological analysis of the heart showed that TRX-1 significantly reduced the severity of EAM, whereas mutant TRX-1 failed to have such an effect, and anti-TRX-1 antibody enhanced the disease markedly. Immunohistochemical analysis showed that TRX-1 significantly suppressed cardiac macrophage inflammatory protein (MIP)-1␣, MIP-2, and 8-hydroxydeoxyguanosine expression and macrophage infiltration into the heart in EAM. Although serum levels of MIP-1␣ were not suppressed by TRX-1 until day 21, both an in vitro chemotaxis chamber assay and an in vivo air pouch model showed that TRX-1 significantly suppressed MIP-1␣-or MIP-2-induced leukocyte chemotaxis. However, real-time reverse transcription-polymerase chain reaction showed that TRX-1 failed to decrease chemokine receptor expression increased in the bone marrow cells of EAM mice. Conclusions-TRX-1 attenuates EAM by suppressing chemokine expressions and leukocyte chemotaxis in mice.

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