Administration of the Ca2+-Activated K+ Channel Activator SKA-31 Improves Endothelial Function in Atherosclerosis-Prone Mice

Vera, Oscar Daniel

Administration of the Ca2+-Activated K+ Channel Activator SKA-31 Improves Endothelial Function in Atherosclerosis-Prone Mice

dc.contributor.advisor	Braun, Andrew
dc.contributor.author	Vera, Oscar Daniel
dc.contributor.committeemember	Thompson, Jennifer
dc.contributor.committeemember	Anderson, Todd
dc.date	2023-11
dc.date.accessioned	2023-06-30T21:30:55Z
dc.date.available	2023-06-30T21:30:55Z
dc.date.issued	2023-06
dc.description.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.
dc.identifier.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.
dc.identifier.uri	https://hdl.handle.net/1880/116686
dc.identifier.uri	https://dx.doi.org/10.11575/PRISM/41528
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Endothelium
dc.subject	Pharmacology
dc.subject	Atherosclerosis
dc.subject	Apoe-/- mice
dc.subject	KCa channel
dc.subject	SKA-31
dc.subject.classification	Physiology
dc.subject.classification	Pharmacology
dc.subject.classification	Immunology
dc.title	Administration of the Ca2+-Activated K+ Channel Activator SKA-31 Improves Endothelial Function in Atherosclerosis-Prone Mice
dc.type	master thesis
thesis.degree.discipline	Medicine – Cardiovascular/Respiratory Science
thesis.degree.grantor	University of Calgary
thesis.degree.name	Master of Science (MSc)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.