Interleukin-10 activates Toll-like receptor 4 and requires MyD88 for cardiomyocyte survival.

Toll-like receptors (TLRs) are important in a variety of inflammatory diseases including acute cardiac disorders. TLR4 innate signaling regulates the synthesis of anti-inflammatory cytokine, interleukin-10 (IL-10) upon TLR4 agonists' re-stimulation. Anti-apoptotic action of IL-10 in cardiac dysfunction is generally accepted but its protective mechanism through TLR4 is not yet understood. We studied the effect of IL-10 in the activation of TLR4 downstream signals leading to cardiomyocytes survival. IL-10 caused a significant increase in the expression of CD14, MyD88 and TLR4. TLR4 activation led to the translocation of the interferon regulatory factor 3 (IRF3) into the nucleus. Phosphorylation of IRF3 enhanced mRNA synthesis for IL-1ß but not TNF-α and was elevated even after removal of IL-10 stimulation. Furthermore, degradation of inhibitory kappa B (IκB) kinase (Ikk) suggested that IκBß was the main activating kinase for IRF3-regulated NF-κB activation and phosphorylation of p65. Phosphorylated NF-κB p65 was translocated into the nucleus. Concomitantly, an increase in Bcl-xL activity inhibited Bax and the proteolytic activity of caspase 3 as well as a decrease in PARP cleavage. An inhibition of MyD88, modulated the above listed responses to IL-10 as there was a decrease in TLR4 and IRF3 and an increase in TNF-α mRNA. This was associated with a decrease in NF-κB p65, Bcl-xL mRNA and protein levels as well as there was an activation of Bax and PARP cleavage independent of caspase 3 activation. These data in cardiomyocytes suggest that IL-10 induced anti-apoptotic signaling involves upregulation of TLR4 through MyD88 activation.

Downregulation of vitamin C transporter SVCT-2 in doxorubicin-induced cardiomyocyte injury.

Vitamin C (Vit C) has been shown to be protective against doxorubicin (Dox)-induced cardiotoxicity. However, Vit C uptake into cardiomyocytes is poorly understood. Furthermore, whether the antioxidant enzyme reserve is enhanced by Vit C is also not known. The present study investigated an influence of Dox on Vit C transporters, expression of endogenous antioxidant reserve as well as enzymes, oxidative stress, and apoptosis in isolated cardiomyocytes. Cardiomyocytes isolated from adult Sprague-Dawley rats were exposed to control (culture medium 199 alone), Dox (10 µM), Vit C (25 µM), and Vit C + Dox for 24 h. Vit C transporter expression and localization, oxidative stress, antioxidant enzymes, and apoptosis were studied. Expression and localization of sodium-dependent vitamin C transporter-2 (SVCT-2) in the sarcolemma was reduced by Dox, but Vit C supplementation was able to blunt this change. There was a decrease in the expression of antioxidant enzymes glutathione peroxidase (GPx), catalase, and Cu/Zn superoxide dismutase (SOD) due to Dox, but only GPx expression was completely prevented and Cu/Zn SOD was partially rescued by Vit C. Dox-induced decrease in antioxidant reserve and increase in oxidative stress were partially mitigated by Vit C. Dox-induced apoptosis was ameliorated by Vit C. It is suggested that cardioprotection offered by Vit C in Dox-induced cardiomyopathy may involve an upregulation of SVCT-2 transporter followed by a reduction in oxidative stress as well as blunting of cardiomyocyte injury.

Modulation of monocrotaline-induced cor pulmonale by grape juice.

The study was designed to test whether the ingestion grape juice (GJ) could modulate monocrotaline (MCT)-induced Cor pulmonale resulting from antioxidant properties. Three-week-old male Wistar rats received GJ (10 mL/kg/day) by gavage for 6 weeks. A single injection of MCT (60 mg/kg body weight intraperitoneally) was administered at the end of the third week. Animals were divided in four groups: control, MCT, GJ, and GJ + MCT. MCT promoted a significant increase in right ventricle (36%) and lung (70%) weight to body weight ratio. There was an increase in the right systolic (38%) as well as in the end diastolic (70%) ventricular pressures. MCT caused a significant decrease in lung endothelial nitric oxide synthase (20%) but increase in lipid peroxidation (13%) and catalase (43%). MCT-induced decrease in the endothelial nitric oxide synthase and increase in the right ventricular end diastolic pressure were prevented by GJ, whereas right systolic ventricular pressure and lung weight to body weight ratio were corrected only partially. MCT-induced increase in heart and right ventricle to body weight ratios was not changed by GJ. GJ blunted MCT-induced increase in lipid peroxidation but had no effect on the changes in catalase and superoxide dismutase activities. GJ appears to offer some protection against MCT-induced Cor pulmonale and right ventricle function changes.

A concise description of cardioprotective strategies in doxorubicin-induced cardiotoxicity.

Doxorubicin (Dox) is frequently used as a frontline chemotherapeutic agent against a variety of cancers. Tremendous progress has been made on its optimal usage over the last 40 years. However, cardiotoxicity still remains a major concern. The great promise in this matter is that the mechanisms leading to antitumor activity appear to be different from those leading to Dox-induced cardiomyopathy. In this regard, various cardioprotective agents have been discussed. Attention should be drawn to probucol, a lipid-lowering agent with potent antioxidant properties, which provides complete protection against Dox-induced cardiomyopathy in rats without interfering with the antitumor properties of Dox in an experimental setting. Clinical trials employing Dox therapy in combination with probucol are needed to determine whether the outstanding findings in animal experiments can be extrapolated to clinical results. We have much further to go before the establishment of cancer therapies without any risk of cardiac side effects.