Impairment of endothelial inwardly rectifying K+ channels in obesity
Date
2024
Authors
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Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Obesity-induced stress affects the vascular endothelium, leading to endothelial dysfunction (ED), a precursor to cardiovascular disease. Despite this, not all vasculature exhibits ED with obesity; visceral adipose arteries (VAA) are impaired, whereas subcutaneous adipose arteries (SAA) retain endothelial function. Our recent study identified that the impairment of inwardly rectifying K+ channel (Kir2.1) is responsible for ED in arteries within visceral adipose tissue (VAT) in cases of obesity while function of Kir2.1 within subcutaneous adipose tissue (SAT) endothelium is unaffected by obesity. However, the mechanisms underlying Kir2.1 impairment remain unclear. Kir2.1 is suppressed by increased levels of fatty acid derivatives within cells in obesity. Obesity is closely associated with elevated levels of circulating fatty acids and previous study has revealed that VAT in obesity is producing more long chain fatty acids (LCFA) and are lipolytically more active. This LCFA requires a transporter to get into the cells where CD36 comes to the play. CD36 is a fatty acid translocase that might have a role in transferring fatty acids from VAT into endothelial cells (EC) and impairing Kir2.1. Therefore, the purpose of the study was 1) to investigate the VAT being a mediator in endothelial Kir2.1 dysfunction in obesity 2) to examine if VAT mediating impairment in Kir2.1 is CD36-dependent. We hypothesized that 1) Endothelial cells exposed to VAT in obesity induces impairment in Kir2.1 and 2) VAT inhibits Kir2.1 current which is driven by CD36 resulting in ED. ☐ We did an in vitro mice study to assess whether VAT and SAT from lean or diet-induced obese mice influenced the function of Kir2.1 channel. Our findings indicated that VAT from obese mice decreased Kir2.1 function with having no effect on channel expression, while adipose tissue (AT) from lean mice as well as SAT from obese mice did not impact Kir2.1 function compared to untreated control cells. Moreover, EC exposed to VAT from obese mice showed a remarkable rise in uptake of fatty acid driven by CD36. Our ex vivo pressure myography experiments on arteries provided further evidence. These studies showed that knocking down of CD36 restored the endothelium's ability to respond to flow by recovering Kir2.1 and eNOS function. Therefore, these results offer novel insights into the role of VAT and the function of CD36 in mediating the impairment of Kir2.1 and leading to ED. ☐ Key words: endothelial dysfunction, inwardly rectifying K+ channel, long chain fatty acid, CD36.
Description
Keywords
Obesity, Endothelial dysfunction, Subcutaneous adipose arteries, Fatty acids