Location: Immunity and Disease Prevention ResearchTitle: Toll-like receptor 4-induced endoplasmic reticulum stress contributes to endothelial dysfunction
|KIM, JEONGA - UNIVERSITY OF ALABAMA|
|JANG, HYUN-JU - UNIVERSITY OF ALABAMA|
Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/30/2015
Publication Date: 9/8/2015
Citation: Kim, J., Jang, H., Hwang, D.H. 2015. Toll-like receptor 4-induced endoplasmic reticulum stress contributes to endothelial dysfunction. American Journal of Physiology. doi: 10.1152/ajpendo.00369.2015.
Interpretive Summary: We examined whether ER stress is involved in SFA-induced impairment of vasodilator actions of insulin. Infusion of palmitate to mice fed high fat diet showed the impairment of vasodilatory response to insulin, which was ameliorated by co-infusion with tauroursodeoxycholic acid (TUDCA), an ER stress suppressor. Together, the results suggest that TLR4-induced ER stress may be an obligatory step mediating the SFA-mediated endothelial dysfunction.
Technical Abstract: Impairment of vasodilator action of insulin is associated with endothelial dysfunction and insulin resistance. Endoplasmic reticulum (ER) stress is implicated as one of the mechanisms for pathophysiology of various cardiometabolic syndromes, including insulin resistance and endothelial dysfunction. Because toll-like receptor 4 (TLR4) plays an important role in pro-inflammatory response and ER stress, we examined whether TLR4-induced ER stress is involved in saturated fatty acid (SFA)-induced endothelial dysfunction. Treatment with SFA (palmitate) stimulated pro-inflammatory responses and ER stress, which was suppressed by knock-down of TLR4 in primary human aortic endothelial cells (HAEC). Then, we examined the role of TLR4 in vasodilatory responses in intact vessels isolated from wild type (WT, C57BL/6) and TLR4-KO mice after feeding high fat (HFD) or normal chow diet (NCD) for 12 weeks. Arterioles isolated from HFD WT mice showed the impairment of vasodilation in response to insulin compared to the arterioles isolated from NCD WT mice. Interestingly, deficiency of TLR4 was protective from HFD-induced impairment of insulin-stimulated vasodilation. There were no differences in acetylcholine (Ach)-, or sodium nitroprusside (SNP)-stimulated vasodilation between groups. Next, we examined whether ER stress is involved in SFA-induced impairment of vasodilator actions of insulin. Infusion of palmitate showed the impairment of vasodilatory response to insulin, which was ameliorated by co-infusion with tauroursodeoxycholic acid (TUDCA), an ER stress suppressor. The results suggest that TLR4-induced ER stress may contribute to the SFA-mediated endothelial dysfunction.