NAD(P)H oxidase-derived reactive oxygen species regulate angiotensin-II induced adventitial fibroblast phenotypic differentiation
ABSTRACT Phenotypic differentiation of adventitial fibroblasts into myofibroblasts is an essential feature of vascular remodeling. The present study was undertaken to test the hypothesis that reactive oxygen species (ROS) are involved in rat adventitial fibroblast differentiation to myofibroblast. Activation of alpha-smooth muscle actin (alpha-SMA) was used as a marker of myofibroblast. Angiotensin II increased intracellular ROS in adventitial fibroblasts that was completely inhibited by the free radical scavenger NAC, the NAD(P)H oxidase inhibitor DPI, and transfection of antisense gp91phox oligonucleotides. Myofibroblast differentiation was prevented by inhibition of ROS generation with DPI, NAC, and antisense gp91phox as shown by decreased expression of alpha-SMA. Angiotensin II rapidly induced phosphorylation of p38 MAPK and JNK, both of which were inhibited by DPI, NAC, antisense gp91phox, and the selective AT1 receptor antagonist, losartan. Inhibiting p38MAPK with SB202190 or JNK with SP600125 also reduced angiotensin II-induced alpha-SMA expression. These findings demonstrate that angiotensin II induces adventitial fibroblast differentiation to myofibroblast via a pathway that involves NADPH oxidase generation of ROS and activation of p38MAPK and JNK pathways.
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ABSTRACT: Reactive oxygen species (ROS) contribute to several aspects of vascular diseases including ischemia-reperfusion injury, scavenging of nitric oxide, or stimulation of inflammation and hypertrophy. NADPH oxidases of the Nox family are differentially expressed in the cardiovascular system, induced or activated by cardiovascular risk factors and importantly contribute to the oxidative burden of vascular diseases. Moreover, NADPH oxidase-derived ROS are important signaling molecules under physiological conditions. In this article, the current knowledge on NADPH oxidase expression, activation, and signaling in the cardiovascular system as well as the impact of risk factors on the function of these proteins will be reviewed. Finally, the contribution of NADPH oxidases to the predominant cardiovascular diseases will be discussed.Free Radical Biology and Medicine 05/2010; 49(5):687-706. DOI:10.1016/j.freeradbiomed.2010.04.030 · 5.71 Impact Factor
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ABSTRACT: The aim of the study was to investigate the cardioprotective effect and mechanism of Crataegus oxycantha (COC) extract, a well-known natural antioxidant-based cardiotonic, against ischemia/reperfusion (I/R) injury. Electron paramagnetic resonance studies showed that COC extract was capable of scavenging superoxide, hydroxyl, and peroxyl radicals, in vitro. The cardioprotective efficacy of the extract was studied in a crystalloid perfused heart model of I/R injury. Hearts were subjected to 30min of global ischemia followed by 45min of reperfusion. During reperfusion, COC extract was infused at a dose rate of 1mg/ml/min for 10min. Hearts treated with COC extract showed a significant recovery in cardiac contractile function, reduction in infarct size, and decrease in creatine kinase and lactate dehydrogenase activities. The expressions of xanthine oxidase and NADPH oxidase were significantly reduced in the treated group. A significant upregulation of the anti-apoptotic proteins Bcl-2 and Hsp70 with simultaneous downregulation of the pro-apoptotic proteins cytochrome c and cleaved caspase-3 was observed. The molecular signaling cascade including phospho-Akt (ser-473) and HIF-1alpha that lead to the activation or suppression of apoptotic pathway also showed a significant protective role in the treatment group. No significant change in phospho-p38 levels was observed. The results suggested that the COC extract may reduce the oxidative stress in the reperfused myocardium, and play a significant role in the inhibition of apoptotic pathways leading to cardioprotection.Phytomedicine: international journal of phytotherapy and phytopharmacology 02/2010; 17(10):744-52. DOI:10.1016/j.phymed.2010.01.009 · 2.88 Impact Factor
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ABSTRACT: Atherosclerosis, the main pathophysiological condition leading to cardiovascular disease (CVD), is now considered to be a chronic inflammatory condition. Statins are the most widely used and promising agents in CVD and are renowned for their pleiotropic lipid lowering independent effects. Statins exert their anti-inflammatory effects on the vascular wall through their implication on a variety of molecular pathways of the innate and adaptive immune system, their impact on the circulating levels of proinflammatory cytokines and their effect on the adhesion molecules. By inhibiting the mevalonate pathway and isoprenoid formation, statins account for the increase of nitric oxide bioavailability and the improvement of vascular and myocardial redox state, by multiple different mechanisms (direct or indirect through LDL lowering). A large number of randomized control trials have well shown that statins help in the primary and secondary prevention of cardiovascular events not only via their lipid lowering effect by due to their anti-inflammatory potential as well. In this article we examine the molecular pathways in which statins are implicated and exert their anti-inflammatory effects, and we are focused specifically in their impact on innate and adaptive immunity. Finally we review the most important clinical data on the role of statins in primary and secondary prevention of cardiovascular events.Journal of the American College of Cardiology 06/2014; 63(23). DOI:10.1016/j.jacc.2014.01.054 · 15.34 Impact Factor