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.
Highlights
Hypertension has been generally associated with structural and functional vascular alterations, and both endothelial dysfunction and increased vasoconstrictor responses are important features of this pathology
Toll-like Receptor 4 (TLR4) mRNA expression was greater in aortic segments from SHRs when compared with those from Wistar rats; this greater expression was reduced after treatment of SHRs with the AT1 receptor antagonist losartan (Fig. 1A), which suggests that Angiotensin II (Ang II) contributes to this increased expression
Immunofluorescence experiments confirm the greater expression of TLR4 in aorta from SHR when compared with Wistar rats; this receptor was localized in the three layers of the vascular wall (Fig. 1C)
Summary
Hypertension has been generally associated with structural and functional vascular alterations, and both endothelial dysfunction and increased vasoconstrictor responses are important features of this pathology. The reduced nitric oxide (NO) bioavailability caused by increased reactive oxygen species (ROS) production would explain these vascular alterations. In this context, in recent years, it has been proposed that low-grade inflammation plays a key role in the development and progression of hypertension [1,2,3,4]. Increased activation of the renin-angiotensin system (RAS) seems to be associated with the inflammatory state observed in hypertension, as well as with its associated vascular alterations [1,5,11,12]. Angiotensin II (Ang II), the effector peptide of RAS, is able to induce Toll-like Receptor 4 (TLR4), and it seems that TLR4dependent signaling pathway contributes to the proinflammatory effects of this humoral factor [13,14,15,16,17,18,19]
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