Abstract:
:Elevated plasma free fatty acids level has been implicated in the development of insulin resistance, inflammation, and endothelial dysfunction in diabetic and nondiabetic individuals. However, the underlying mechanisms still remain to be defined. Herein, we investigated the effect of palmitic acid (PA), the most abundant saturated fatty acid in the human body, on small-conductance Ca2+-activated potassium channels (KCa2.3)-mediated relaxation in rodent resistance arteries and the underlying molecular mechanism. The effect of PA on KCa2.3 in endothelium was evaluated using real-time PCR, Western blotting, whole-cell patch voltage-clamp, wire and pressure myograph system, and reactive oxygen species (ROS) were measured by using dihydroethidium and 2', 7'-dichlorofluorescein diacetate. KCa2.3-mediated vasodilatation responses to acetylcholine and NS309 (agonist of KCa2.3 and KCa3.1) were impaired by incubation of normal mesenteric arteries with 100 μM PA for 24 h. In cultured human umbilical vein endothelial cells (HUVECs), PA decreased KCa2.3 current and expression at mRNA and protein levels. Incubation with the NADPH oxidase (Nox) inhibitor dibenziodolium (DPI) partly inhibited the PA-induced ROS production and restored KCa2.3 expression. Inhibition of either p38-MAPK or NF-κB using specific inhibitors (SB203580, SB202190 or Bay11-7082, pyrrolidinedithiocarbamate) attenuated PA-induced downregulation of KCa2.3 and inhibition of p38-MAPK also attenuated PA-induced phosphorylation of NF-κB p65. Furthermore, DPI reversed the increment of phospho-p38-MAPK by PA. These results demonstrated that PA downregulated KCa2.3 expressions via Nox/ROS/p38-MAPK/NF-κB signaling leading to endothelial vasodilatory dysfunction.
journal_name
Exp Cell Resjournal_title
Experimental cell researchauthors
Wang Y,Wang XJ,Zhao LM,Pang ZD,She G,Song Z,Cheng X,Du XJ,Deng XLdoi
10.1016/j.yexcr.2019.111552subject
Has Abstractpub_date
2019-10-15 00:00:00pages
111552issue
2eissn
0014-4827issn
1090-2422pii
S0014-4827(19)30404-5journal_volume
383pub_type
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