Administration of the Ca2+-Activated K+ Channel Activator SKA-31 Improves Endothelial Function in Atherosclerosis-Prone Mice
Date
2023-06
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Abstract
Atherosclerosis is a major risk factor for cardiovascular disease and is induced by hyperlipidemia and endothelial dysfunction, leading to fatty plaque formation and impaired vascular function. Recent studies have reported that pharmacological activation of endothelial Ca2+-activated K+ channels (KCa2.3 and KCa3.1) can oppose endothelial dysfunction by enhancing endothelium-dependent vasodilation in animal models of aging and type 2 diabetes. In my project, I hypothesized that improving endothelial function via pharmacological enhancement of endothelial KCa2.3 and KCa3.1 channels with SKA-31 would mitigate the development and/or severity of atherosclerosis.
Experimentally, I utilized apoliproprotein E knockout (Apoe-/-) mice subjected to a high fat diet (HFD) as a model of human aortic atherosclerosis. Male Apoe-/- mice were administered one of three daily oral treatments for 12 weeks: the KCa channel activator SKA-31 (10 mg/kg), the KCa3.1 channel blocker senicapoc (40 mg/kg), or drug vehicle alone. Cardiac function was assessed by echocardiography, atherosclerotic lesions in the aorta were visualized by Oil Red O (ORO) staining and immunohistochemistry, abdominal aortic contractility and relaxation were measured by wire myography, and select tissues were evaluated by histology. At ~20 weeks of age, left ventricular ejection fraction and fractional shortening were not different in Apoe-/- mice following treatment with either SKA-31 or senicapoc vs. vehicle. ORO staining of the thoracic aorta and aortic arch revealed that neither SKA-31 nor senicapoc treatments decreased plaque formation vs. vehicle. Aortae from sex/age matched wild-type (WT) mice showed no visible plaque formation. Phenylephrine (PE)-evoked contraction of abdominal aortic rings was similar in WT and vehicle/drug treated Apoe-/- mice. Conversely, endothelium-dependent,
acetylcholine-induced maximal relaxation was significantly enhanced in PE-constricted aortic rings from SKA-31-treated mice (~81%) vs. vehicle (~53%, P<0.0001), whereas senicapoc administration had no beneficial effect. Maximal relaxation induced by the endothelium-independent vasodilator sodium nitroprusside was similar in WT and vehicle/drug treated Apoe-/- mice. Finally, neither SKA-31 nor senicapoc treatments produced adverse effects on histological features of the brain, liver, and kidneys from Apoe-/- mice. In summary, my results indicate that enhancement of KCa channel activity in vivo via SKA-31 administration improved aortic endothelial function without decreasing plaque formation.
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Keywords
Endothelium, Pharmacology, Atherosclerosis, Apoe-/- mice, KCa channel, SKA-31
Citation
Vera, O. D. (2023). Administration of the Ca2+-activated K+ channel activator SKA-31 improves endothelial function in atherosclerosis-prone mice (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.