Oxidized LDL enhances Gq signaling and aldosterone production by angiotensin II via the AT1-LOX-1 receptor complex in adrenal cells
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Bibliographic record
Abstract
We previously reported that oxidized low-density lipoprotein (oxLDL) activates the angiotensin II (AII) type 1 receptor (AT1) through the lectin-like oxLDL receptor (LOX-1)-AT1 complex. While oxLDL alone does not activate G protein αq (Gq), its simultaneous binding with AII alters AT1 structure, enhancing Gq activation. We investigated this interaction's effect on aldosterone production in adrenal glands. Human adrenal cells (H295R) were treated with vehicle, oxLDL, AII, or a combination of oxLDL and AII. Gq signaling was assessed using inositol monophosphate (IP1) assays, Ca influx using Fura2, and aldosterone synthesis gene expression using qRT-PCR. Wild-type (WT) and LOX-1 knockout (KO) mice were fed a normal diet (ND) or high-fat diet (HFD) in vivo to elevate oxLDL levels, followed by subcutaneous AII or saline infusion for 4 weeks (long-term) or 3 days (short-term). In H295R cells, oxLDL alone did not induce IP1 production; however, AII-induced IP1 and Ca influx were enhanced by oxLDL. These effects were abolished by LOX-1 siRNA. Co-administration of oxLDL and AII upregulated aldosterone synthesis genes, such as CYP11B2; this effect was suppressed by a Gq inhibitor. In vivo, long-term AII and HFD administration increased adrenal CYP11B2 expression but not serum aldosterone levels. Conversely, short-term AII and oxLDL administration elevated serum aldosterone levels, but not CYP11B2 expression. These effects were absent in LOX-1 KO mice. Blood pressure was unaffected by HFD or oxLDL in both models. In conclusion, OxLDL enhances AII-induced aldosterone production in adrenal glands through LOX-1-AT1 interaction, although its impact on blood pressure regulation remains unclear. Oxidized LDL enhances Gq signaling and aldosterone production by angiotensin II via the AT1-LOX-1 receptor complex in adrenal cells. LOX-1 amplifies angiotensin II-induced aldosterone synthesis by modulating AT1 receptor signaling in adrenal glands. Co-stimulation with oxLDL enhances Gq activation via LOX-1-AT1 interaction, potentially through AT1 unique conformational changes. These findings underscore the interplay between dyslipidemia and RAAS in promoting hypertension and cardiovascular diseases.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it