Abstract
Introduction: Our 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. Methods: In this study we developed a new CRISPR mouse model, originated from our molecular dynamics research for the Kir 2.1 channel. This model Kir2.1 L222I , 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 -/- Kir2.1 L222I . 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. Results: A lack of cholesterol sensitivity of Kir2.11 L222I was functionally confirmed in endothelial cells freshly isolated from mesenteric arteries of Kir2.1 L222I and ApoE -/- Kir2.1 L222I mice. We found that ApoE -/- Kir2.1 L222I 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 -/- Kir2.1 L222I mice respectively. The effect on the lesion area in the descending aorta was even more pronounced: 16.5 ±2.1% (n:8) in ApoE -/- to 5.6± 1.3% (n:8) in ApoE -/- Kir2.1 L222I . 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 -/- Kir2.1 L222I 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. Conclusion: Our data suggest that cholesterol-induced suppression of Kir2.1 is an important contributor to the development of atherosclerosis.
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