Poly (I:C) impairs NO donor-induced relaxation by overexposure to NO via the NF-kappa B/iNOS pathway in rat superior mesenteric arteries

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): Makoto Ando, Takayuki Matsumoto, Kumiko Taguchi, Tsuneo Kobayashi
Recent studies have suggested a link between vascular dysfunction and innate immune activation including toll-like receptors (TLRs), but the detailed mechanism remains unclear. Here we investigated whether poly (I:C) [a synthetic double-strand RNA recognized by TLR3, melanoma differentiation-associated gene 5 (MDA5), and retinoic acid-inducible gene I (RIG-I)] affected nitric oxide (NO)/cGMP-related vascular relaxation, one of the major cascades of relaxation, in rat superior mesenteric arteries. Using organ-cultured arteries, we found that poly (I:C) (30μg/mL for approximately 1 day) markedly reduced sodium nitroprusside (SNP)-induced relaxation (vs. vehicle); this was prevented by co-treatment with a TLR3 inhibitor. Relaxation induced by 8-Br cGMP (a phosphodiesterase (PDE)-resistant cGMP analogue) and the expression of proteins related to NO/cGMP signaling did not differ between vehicle- and poly (I:C)-treated groups. When PDEs were inhibited by IBMX (a nonselective PDE inhibitor), the SNP-induced relaxation was still greatly reduced in poly (I:C)-treated arteries (vs. vehicle). Poly (I:C) reduced SNP-stimulated cGMP production, but increased NO production and iNOS expression (vs. vehicle). The impairment of SNP-induced relaxation by poly (I:C) was prevented by co-treatment with either iNOS or a nuclear factor-kappa B (NF-κB) inhibitor. This effect induced by poly (I:C) appeared to be independent of oxidative stress. The SNP-induced relaxation was reduced in freshly isolated arteries by pre-incubation with SNP in a concentration-dependent manner. Poly (I:C) did not alter protein levels of TLR3, TRIF/TICAM-1, or phospho-IRF3/IRF3, whereas RIG-I and MDA5 were significantly upregulated (vs. vehicle). These results suggest that poly (I:C) impairs NO donor-induced relaxation in rat superior mesenteric arteries via overexposure to NO produced by the NF-κB/iNOS pathway.

Graphical abstract

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