Oxidized LDL enhances Gq signaling and aldosterone production by angiotensin II via the AT1-LOX-1 receptor complex in adrenal cells

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.