Enhancement of Endothelial KCa Channel Activity as a Novel Strategy to Oppose Atherosclerosis
Bibliographic record
Abstract
Atherosclerosis is a harmful cardiovascular condition in which low‐density lipoprotein cholesterol (LDL‐C) elevates in the blood, passes through the arterial endothelium, and promotes endothelial dysfunction (ED). ED can facilitate fatty plaque formation, which decreases intraluminal arterial diameter and blood flow, and increases arterial stiffness. A hallmark feature of ED is decreased bioavailability of nitric oxide (NO), a pluripotent compound with vasodilatory effects, along with anti‐inflammatory and anti‐proliferative actions in the arterial wall. Our group has previously reported that pharmacological activation of endothelial Ca 2+ ‐activated K + channels, i.e. KCa2.3 and KCa3.1, can reverse ED, in part by enhancing endothelial NO production. Given the contributions of ED and NO in atherosclerosis, we hypothesize that enhancing endothelial function will mitigate the development and/or severity of atherosclerosis. The aim of this proof‐of‐concept study is to determine whether prolonged administration of the KCa channel activator SKA‐31 in vivo can mitigate atherosclerosis by decreasing ED, arterial stiffness and/or fatty plaque formation. In this presentation, I will describe preliminary data obtained during the initial phase of this study. To mimic human atherosclerosis, we are using male Apoe knockout (Apoe‐/‐) mice, which begin to develop signs of progressive aortic injury at ~8 weeks of age. Experimentally, Apoe‐/‐ mice on a regular chow diet receive one of three daily treatments for 16 weeks: SKA‐31 (10 mg/kg), the KCa3.1 channel blocker senicapoc (40 mg/kg) or drug vehicle alone. As previous studies have reported that KCa3.1 channel blockers can reduce atherosclerotic events, we are using this treatment condition as a benchmark in our study. Drugs are formulated in miglyol and condensed milk, which is readily ingested by the mice. Plasma LDL‐C levels are being measured to determine whether drug treatment modifies the levels of this important pathogenic molecule. Echocardiography is being used to measure standard cardiac function, along with aortic flow and pulse wave velocity as markers of arterial stiffness. Following euthanasia, vasodilatory responses of the aorta are examined by wire myography to determine whether drug treatment improves endothelial function. Histopathological analyses are being performed to elucidate aortic structure and integrity (with H&E staining) and the extent of atherosclerotic plaque formation in the aorta (with Oil Red O staining). Lastly, macrophage proliferation in the aortic wall will be assessed by immunocytochemistry, as macrophages proliferate rapidly in fatty plaque sites. Positive results from this study will facilitate future research to investigate the underlying cellular mechanisms by which endothelial KCa channel activation opposes atherogenesis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".