Angiotensin II induces inflammatory response partly via toll-like receptor 4-dependent signaling pathway in vascular smooth muscle cells

Yuanyuan Ji, Juntian Liu, Zhidong Wang, Na Liu
Cellular Physiology and Biochemistry 2009, 23 (4-6): 265-76
Angiotensin (Ang II) plays an important role in atherosclerosis through proinflammatory effect. Toll-like receptor 4 (TLR4) may mediate inflammatory response. It is unknown whether TLR4 mediates the proinflammatory effect of Ang II. Thus, we observed the role and signaling pathway of TLR4 in Ang II-induced inflammation in rat vascular smooth muscle cells (VSMCs). Ang II and LPS stimulated TNF-alpha secretion and inhibited 6-keto-PGF(1alpha ) production, upregulated MMP-9 and downregulated PPARgamma and PPARalphain rat VSMCs. Ang II also distinctly upregulated TLR4 expression in the cells. Pretreatment of the cells with anti-TLR4 antibody prior to Ang II stimulation significantly diminished the effects of Ang II. These suggest that Ang II stimulates VSMCs to produce inflammation through regulation of the proinflammatory and the antiinflammtory factors via TLR4-dependent mechanism. The further investigations showed that AT1 receptor antagonist losartan or ERK1/2 inhibitor PD098059 inhibited Ang II-induced TLR4 expression, TLR4 inhibitor prevented Ang II- induced IP-10 expression, anti-IP-10 antibody partly abolished Ang II- induced PKC increase, and PKC inhibitor chelerythrine suppressed Ang II- induced NF-kappaB expression. These demonstrate that TLR4-mediated proinflammatory effect of Ang II in VSMCs involves AT1/ERK1/2/TLR4/IP-10/ PKC/NF-kappaB pathway. Our results provide the evidence that Ang II induces inflammatory response involved in pathogenesis of atherosclerosis partly via TLR4- dependent signaling pathway in VSMCs.

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