Toll-like receptor 4 (TLR4) is key regulators of both innate and adaptive immune responses. TLR4 recognizes pathogen-associated molecular patterns (PAMPs) and activates the inflammatory cells. The function of TLR4 in atherosclerosis has been investigated in mouse knockout studies and epidemiological studies of human TLR4 polymorphisms. These studies have shown that TLR4 function affects the initiation and progression of atherosclerosis. This article reviews the biological functions and clinical implications of TLR4 in atherosclerosis.
Background and purpose: Although the main therapeutic effect of angiotensin AT1 receptor antagonists is to decrease blood pressure, they also exert anti-inflammatory effects in the cardiovascular system. However, the underlying mechanisms remain unclear. We investigated the inhibitory effect of AT1 antagonists on the chemokine monocyte chemoattractant protein 1 (MCP-1) and its receptor C-C chemokine receptor 2 (CCR2) in rat monocytes and aortas. Experimental approach: Spontaneous hypertensive rats (SHRs) were treated with the AT1 antagonists losartan or telmisartan for 4 weeks, and Wistar-Kyoto rats (WKYs) were used as normotensive controls. Systolic arterial pressure was measured, and the number of macrophages in the aortic vessel wall was assessed by anti-ED-1 antibody immunolabelling. Key results: Compared with WKYs, SHRs showed significantly increased ED-1 positive macrophages in the aortic wall, which were decreased after high doses of losartan or telmisartan. Low doses of losartan did not improve blood pressure significantly as did the high doses, but markedly decreased macrophage infiltration in the vessel wall. AT1 antagonists, particularly at high doses, improved aortic remodeling in SHR. At the molecular level, AT1 antagonists attenuated the expression of MCP-1 and CCR2 in the aorta and peripheral blood monocytes and lowered the serum level of MCP-1. In addition, Western blotting showed that AT1 antagonists inhibited the phosphorylation of Akt in mouse monocytes. Conclusions and implications: AT1 antagonism inhibited vessel wall inflammation and inhibition of PI3K/Akt may be involved in the modulation of the MCP-1/CCR2 system by AT1 antagonists in SHRs.
We investigated whether oxygen radicals generated during ischemia-reperfusion trigger postischemic inflammation in the heart. Closed-chest dogs underwent 90-min coronary artery occlusion, followed by 1- or 3-h reperfusion: 10 dogs received the cell-permeant oxygen radical scavenger N-(2-mercaptopropionyl)-glycine (MPG; 8 mg x kg(-1) x h(-1) intracoronary) beginning 5 min before reperfusion, and 9 dogs received vehicle. Blood flow (microspheres), intercellular adhesion molecule (ICAM)-1 protein expression (immunohistochemistry), ICAM-1 gene activation (Northern blotting), nuclear DNA binding activity of nuclear factor (NF)-kappaB and AP-1 (electrophoretic mobility shift assays), and neutrophil (PMN) accumulation (myeloperoxidase activity) were assessed in myocardial tissue samples. ICAM-1 protein expression was high in vascular endothelium after ischemia-reperfusion but was markedly reduced by MPG. MPG treatment also markedly decreased expression of ICAM-1 mRNA and tissue PMN accumulation. Nuclear DNA binding activities of NF-kappaB and AP-1, increased by ischemia-reperfusion, were both markedly decreased by MPG at 1 h of reperfusion. However, by 3 h, AP-1 activity was only modestly reduced by MPG and NF-kappaB activity was not significantly different from ischemic-reperfused controls. These results suggest that oxygen radicals generated in vivo during reperfusion trigger early activation of NF-kappaB and AP-1, resulting in upregulation of the ICAM-1 gene in vascular endothelium and subsequent tissue accumulation of activated PMNs.
The hypnotic agent propofol is effective for the induction and maintenance of anesthesia. However, recent studies have shown that propofol administration is related to arrhythmias. Propofol displays both pro- and anti-arrhythmic effects in a concentration-dependent manner. Data indicate that propofol can convert supraventricular tachycardia and ventricular tachycardia and may inhibit the conduction system of the heart. The mechanism of the cardiac effects remains poorly defined and may involve ion channels, the autonomic nervous system and cardiac gap junctions. Specifically, sodium, calcium and potassium currents in cardiac cells are suppressed by clinically relevant concentrations of propofol. Propofol shortens the action potential duration (APD) but lessens the ischemia-induced decrease in the APD. Furthermore, propofol suppresses both sympathetic and parasympathetic tone and preserves gap junctions during ischemia. All of these effects cumulatively contribute to the antiarrhythmic and proarrhythmic properties of propofol.
The RVOT pacing in AV block patients over 1 year may be superior to RVA pacing in terms of regional LV performance, LV global electromechanical delay, and IVMD, although intraventricular dyssynchrony and LV volumes do not differ. Larger trials with clinical endpoints are warranted to conclusively define the advantages of RVOT or RV septal pacing.
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