We demonstrate that during inflammatory responses the nuclear factor kappa B (NF-κB) induces the synthesis of melatonin by macrophages and that macrophage-synthesized melatonin modulates the function of these professional phagocytes in an autocrine manner. Expression of a DsRed2 fluorescent reporter driven by regions of the aa-nat promoter, that encodes the key enzyme involved in melatonin synthesis (arylalkylamine-N-acetyltransferase), containing one or two upstream κB binding sites in RAW 264.7 macrophage cell lines was repressed when NF-κB activity was inhibited by blocking its nuclear translocation or its DNA binding activity or by silencing the transcription of the RelA or c-Rel NF-κB subunits. Therefore, transcription of aa-nat driven by NF-κB dimers containing RelA or c-Rel subunits mediates pathogen-associated molecular patterns (PAMPs) or pro-inflammatory cytokine-induced melatonin synthesis in macrophages. Furthermore, melatonin acts in an autocrine manner to potentiate macrophage phagocytic activity, whereas luzindole, a competitive antagonist of melatonin receptors, decreases macrophage phagocytic activity. The opposing functions of NF-κB in the modulation of AA-NAT expression in pinealocytes and macrophages may represent the key mechanism for the switch in the source of melatonin from the pineal gland to immune-competent cells during the development of an inflammatory response.

Moreira JB, Bechara LR, Bozi LH, Jannig PR, Monteiro AW, Dourado PM, Wisløff U, Brum PC. High-versus moderate-intensity aerobic exercise training effects on skeletal muscle of infarcted rats. J Appl Physiol 114: 1029 -1041, 2013. First published February 21, 2013 doi:10.1152/japplphysiol.00760.2012.-Poor skeletal muscle performance was shown to strongly predict mortality and long-term prognosis in a variety of diseases, including heart failure (HF). Despite the known benefits of aerobic exercise training (AET) in improving the skeletal muscle phenotype in HF, the optimal exercise intensity to elicit maximal outcomes is still under debate. Therefore, the aim of the present study was to compare the effects of highintensity AET with those of a moderate-intensity protocol on skeletal muscle of infarcted rats. Wistar rats underwent myocardial infarction (MI) or sham surgery. MI groups were submitted either to an untrained (MI-UNT); moderate-intensity (MI-CMT, 60% V O2 max); or matched volume, high-intensity AET (MI-HIT, intervals at 85% V O2 max) protocol. High-intensity AET (HIT) was superior to moderate-intensity AET (CMT) in improving aerobic capacity, assessed by treadmill running tests. Cardiac contractile function, measured by echocardiography, was equally improved by both AET protocols. CMT and HIT prevented the MI-induced decay of skeletal muscle citrate synthase and hexokinase maximal activities, and increased glycogen content, without significant differences between protocols. Similar improvements in skeletal muscle redox balance and deactivation of the ubiquitin-proteasome system were also observed after CMT and HIT. Such intracellular findings were accompanied by prevented skeletal muscle atrophy in both MI-CMT and MI-HIT groups, whereas no major differences were observed between protocols. Taken together, our data suggest that despite superior effects of HIT in improving functional capacity, skeletal muscle adaptations were remarkably similar among protocols, leading to the conclusion that skeletal myopathy in infarcted rats was equally prevented by either moderate-intensity or high-intensity AET. atrophy; heart failure; proteasome; oxidative stress SKELETAL MUSCLE ABNORMALITIES in systemic diseases have been described for decades (9, 14, 29, 52), including in heart failure (HF). Capillary rarefaction, switch from type I (oxidative) to type II (glycolytic) fibers, impaired metabolism, and skeletal muscle atrophy have been shown in human and experimental models of HF (14,21,29,43,49,52). This maladaptation seems to impair skeletal muscle performance, which was proposed as the main determinant of exercise capacity in patients with HF (21,32,40). Additionally, skeletal muscle loss was shown to be an independent predictor of mortality in HF (3).Recent efforts by researchers have identified possible intracellular mechanisms underlying the skeletal muscle abnormalities in cardiovascular diseases, and promising targets such as metabolic enzymes, calcium handling-related proteins, antioxidant scavengers, and in...

This study showed that aerobic training promotes an increase in the expression of miRNA-126 and that this may be related to exercise-induced cardiac angiogenesis, by indirect regulation of the VEGF pathway and direct regulation of its targets that converged in an increase in angiogenic pathways, such as MAPK and PI3K/Akt/eNOS.

Endothelial cells produce NO by activation of constitutive nitric oxide synthase (NOS) and transcription of inducible NOS (iNOS). We have previously shown that melatonin, in the nanomolar range, inhibits activation of constitutive NOS, and in the present paper, we evaluated whether it could interfere with the expression of iNOS, which is activated by lipopolysaccharide (LPS), a major component of gram-negative bacteria cell walls. Primary cultures of rat endothelial cells were loaded with fluorescent probe for NO detection. Nuclear factor kappa B (NF-kappaB) translocation in endothelial cells elicited by LPS was measured by electromobility shift assay, and the vasodilation of aortic rings was accessed by recording isometric contraction. Melatonin in a micromolar but not in a nanomolar range inhibits the NO production induced by LPS. This effect is not dependent on the activation of G protein-coupled melatonin receptors. The nuclear NF-kappaB translocation is a process necessary for iNOS transcription, and melatonin also inhibits its translocation. LPS induced vasodilation only in endothelium-intact aortic rings, and melatonin (10 mum) inhibits the vasodilation. Here, we show that concentrations compatible with nocturnal melatonin surge (nm) did not interfere with the activity of iNOS. Considering that micromolar melatonin concentrations could be locally achieved through production by activated immune competent cells, extra-pineal melatonin could have a protective effect against tissue injury. We propose that melatonin blocked the LPS-induced vasodilation by inhibiting the NF-kappaB pathway. Finally, we propose that the effect of melatonin on vascular reactivity is one of the mechanisms that underlies the protective effect of this indolamine against LPS.