Aumento da Expressão do receptor tipo Toll 4 pela angiotensina II contribui para a hipertensão e disfunção vascular através da produção de espécies reativas de oxigênio.
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2014-09-22
Autores
Batista, Priscila Rossi de
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Universidade Federal do Espírito Santo
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Hypertension is considered as a chronic inflammatory disease, with adaptive immunity being an important mediator of this process. Toll like receptor 4 (TLR4) - that triggers the innate immunity - 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 the increased activity of the renin-angiotensin system (RAS) contributes to hypertension and its associated vascular damage. For this, we used the following groups: Wistar and SHR controls; SHR losartan (losartan 15 mg/kg•day); Wistar and SHR IgG (non-specific IgG 2a, 1 μg/day); SHR anti-TLR4 (antibody anti-TLR4, 1 μg/day). We also used aortic segments and vascular smooth muscle cels (VSMCs) from Wistar and SHRs controls. TLR4 mRNA levels were greater in aortic segments and VSMCs from SHRs compared with Wistar rats; losartan treatment reduced those levels in 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 in aortic rings; 2) increased the potentiation of phenylephrine contraction after endothelium removal; and 3) abolished the inhibitory effects of tiron, apocynin and catalase on 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. CLI095, a TLR4 inhibitor, mitigated the increases in NOX-4, NADPH oxidase activity, superoxide anion production, COX-2 gene and protein expression, 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 contributes to the endothelial dysfunction associated to this pathologic process. These results suggest that TLR4 and innate immunity may play a role in hypertension and its associated end-organ damage.
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BATISTA, P. R., Aumento da Expressão do receptor tipo Toll 4 pela angiotensina II contribui para a hipertensão e disfunção vascular através da produção de espécies reativas de oxigênio.
2014. Tese (Doutorado em Ciências Fisiológicas) - Universidade Federal do Espírito Santo, Centro de Ciências da Saúde, Vitória, 2014.