Abstract 15088: Cholesterol-Induced Suppression of Kir2.1 Contributes to the Development of Atherosclerosis

• Published in: Circulation (New York, N.Y.) N.Y.), 2022-11, Vol.146 (Suppl_1), p.A15088-A15088
• Main Authors: Granados, Sara T, Do Couto, Natalia, Fancher, Ibra, Levitan, Irena
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.146.suppl_1.15088

IntroductionOur recent studies demonstrated that cholesterol sensitivity of inwardly-rectifying K+ channels (Kir2.1) contributes to the impairment of flow-induced vasodilation (FIV) in resistance arteries. MethodsIn this study we developed a new CRISPR mouse model, originated from our molecular dynamics research for the Kir 2.1 channel. This model Kir2.1L222I, has a point mutation (L222I) that renders the channel cholesterol insensitive. We also crossed our new CRISPR model with a dyslipidemic ApoE-/- mice resulting in a ApoE-/-Kir2.1L222I. We evaluated Kir2.1 channel function with patch clamp for both models. We then placed our mice on a high fat (42% kcal from fat) diet (HFD) from 12 -14 weeks and analyzed atherosclerotic lesions with Oil Red O in En Face aortas and cross sections of carotid arteries for both female and male mice. We also documented weight gain, food consumption and blood biochemistry. ResultsA lack of cholesterol sensitivity of Kir2.11L222I was functionally confirmed in endothelial cells freshly isolated from mesenteric arteries of Kir2.1L222I and ApoE-/-Kir2.1L222I mice. We found that ApoE-/-Kir2.1L222I mice have significant reduction in the area of atherosclerotic lesions in their aortas, as compared to ApoE-/- mice. This phenomenon was observed both in the aortic arch and in the descending aorta. Specifically, the lesion areas in the arch were 37.2± 1.87% (n:8) vs. 20.3 ±2.3% (n:8) in ApoE-/- vs. ApoE-/-Kir2.1L222I mice respectively. The effect on the lesion area in the descending aorta was even more pronounced16.5 ±2.1% (n:8) in ApoE-/- to 5.6± 1.3% (n:8) in ApoE-/-Kir2.1L222I. The same effect was observed in males and females. In addition, we also analyzed the lesion areas and stenosis in carotid arteries of the same mice and found that ApoE-/-Kir2.1L222I mice are also partially protected, as compared to ApoE-/-. However, no differences were found in the levels of LDL, HDL and total cholesterol between these mice. ConclusionOur data suggest that cholesterol-induced suppression of Kir2.1 is an important contributor to the development of atherosclerosis.