Toll-Like Receptor 4 Upregulation by Angiotensin II Contributes to Hypertension and Vascular Dysfunction through Reactive Oxygen Species Production

Abstract

Hypertension is considered as a low-grade inflammatory disease, with adaptive immunity being an important mediator of this pathology. TLR4 may have a role in the development of several cardiovascular diseases; however, little is known about its participation in hypertension. We aimed to investigate whether TLR4 activation due to increased activity of the renin-angiotensin system (RAS) contributes to hypertension and its associated endothelial dysfunction. For this, we used aortic segments from Wistar rats treated with a non-specific IgG (1 µg/day) and SHRs treated with losartan (15 mg/kg·day), the non-specific IgG or the neutralizing antibody anti-TLR4 (1 µg/day), as well as cultured vascular smooth muscle cells (VSMC) from Wistar and SHRs. TLR4 mRNA levels were greater in the VSMC and aortas from SHRs compared with Wistar rats; losartan treatment reduced those levels in the SHRs. Treatment of the SHRs with the anti-TLR4 antibody: 1) reduced the increased blood pressure, heart rate and phenylephrine-induced contraction while it improved the impaired acetylcholine-induced relaxation; 2) increased the potentiation of phenylephrine contraction after endothelium removal; and 3) abolished the inhibitory effects of tiron, apocynin and catalase on the phenylephrine-induced response as well as its enhancing effect of acetylcholine-induced relaxation. In SHR VSMCs, angiotensin II increased TLR4 mRNA levels, and losartan reduced that increase. CLI-095, a TLR4 inhibitor, mitigated the increases in NAD(P)H oxidase activity, superoxide anion production, migration and proliferation that were induced by angiotensin II. In conclusion, TLR4 pathway activation due to increased RAS activity is involved in hypertension, and by inducing oxidative stress, this pathway contributes to the endothelial dysfunction associated with this pathology. These results suggest that TLR4 and innate immunity may play a role in hypertension and its associated end-organ damage.

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

“…This may stem from the known association between TLR4 and angiotensin II, which some have classified as a DAMP (Erridge, 2010;McCarthy et al, 2014). TLR4 significantly contributes to the etiology of vascular dysfunction and high blood pressure in various experimental models of hypertension, such as the spontaneously hypertensive rat (SHR) and rats with angiotensin II-induced hypertension (De Batista et al, 2014;Hernanz et al, 2015). Similarly, TLR4 plays a role in paraventricular nucleusmediated autonomic dysfunction in SHR (Dange et al, 2015) and in rats with angiotensin II-induced hypertension (Dange et al, 2014).…”

Treatment with high dose of atorvastatin reduces vascular injury in diabetic rats

“…The influence of the endothelium on the response to phenylephrine was investigated after the endothelium has been mechanically removed [21]. This was confirmed by the inability of 10 mM acetylcholine to produce relaxation (represented by E À ).…”

“…Segments of thoracic aorta were mounted in isolated tissue chambers as previously described [21]. After the smooth muscle and endothelial integrity tests, increasing concentrations of phenylephrine (0.1 nM to 30 mM) were applied to get the concentration-response curve.…”

Pioglitazone Reduces Vascular Lipid Accumulation in Angiotensin II-Induced Hypertensive Rat

“…In addition, angiotensin II significantly reduced the expression of FAS mRNA (32 5%, p 0.05 ver- . Under an activated renin-angiotensin system, NADPH oxidase-mediated superoxide production may reduce NO bioavailability and induce vascular dysfunction 25) . Our current study demonstrated that in the angiotensin IIinfused rat, DHE signals indicating superoxide production were increased at the site of lipid deposition and were mainly localized in ED-1-positive monocytes/macrophages.…”