Administration of the KCa channel activator SKA-31 improves endothelial function in the aorta of atherosclerosis-prone mice

Abstract

Atherosclerosis is a major risk factor for cardiovascular disease and is induced by hyperlipidemia and endothelial dysfunction (ED), leading to fatty plaque formation and impaired vascular function. Pharmacological activation of endothelial Ca 2+ -activated K + channels (KCa2.3 and KCa3.1) can oppose ED by enhancing endothelium-dependent vasodilation.We hypothesized that improving endothelial function will mitigate the development and/or severity of atherosclerosis in Apoe knockout (Apoe-/-) mice. Administration of the KCa channel activator SKA-31 was utilized to improve endothelial function in vivo.Experimentally, 8-week-old male Apoe-/- mice on a high fat diet (HFD) 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. Pharmacological inhibition of KCa3.1 channels is reported to reduce atherosclerosis in Apoe-/- mice and was utilized as a benchmark. Cardiac function was assessed by echocardiography under isoflurane anesthesia. Atherosclerotic lesions in the thoracic aorta were visualized by Oil-Red-O staining, and abdominal aortic contractility and relaxation were measured by wire myography in Apoe-/- mice and age/sex-matched wild-type C57BL/6 mice.At the end of drug treatment, left ventricular (LV) ejection fraction, fractional shortening, and LV posterior wall thickness were not different in Apoe-/- mice treated with either SKA-31 or senicapoc compared with vehicle. Oil-Red-O staining of the thoracic aorta and aortic arch revealed fatty plaque formation in Apoe-/- mice (~15% of area) compared with WT controls (<1% of area), but neither SKA-31 nor senicapoc treatments reduced plaque formation vs. vehicle. Phenylephrine (PE)-evoked contraction of abdominal aortic rings was similar in WT and vehicle/drug treated Apoe-/- mice. Conversely, endothelium-dependent, acetylcholine-induced relaxation was significantly enhanced in PE-constricted aortic rings from SKA-31-treated mice (mean ± SD, 75.6 ± 21.1 %) vs. vehicle (51.2 ± 11.9 %, p=0.0024). Acetylcholine-induced relaxation was not improved by senicapoc administration. Relaxation induced by the smooth muscle vasodilator sodium nitroprusside was similar in WT and vehicle/drug treated Apoe-/- aortic rings. Summary: SKA-31 administration improved aortic endothelial function without reducing lesion density. Future studies will examine how SKA-31 improves endothelium-dependent relaxation and whether enhanced KCa channel activity (with SKA-31) in combination with lipid-lowering drugs (e.g., statins) can mitigate atherosclerosis more effectively. Enhancement of endothelial KCa channel activity may thus represent a viable stand-alone or “add-on” strategy to reduce morbidity and mortality associated with ED and atherosclerosis. Funding provided by the CIHR and NSERC This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.