Ihara Jittoku, Huang Yibin, Takami Yoichi, Guo Yu, Takahashi Toshimasa, Kakino Akemi, Nozato Yoichi, Wang Cheng, Wang Ziwei, Liu Weidong, Yin Nanxiang, Ohara Ryoichi, Hara Akitoshi, Takeshita Hikari, Rakugi Hiromi, Sawamura Tatsuya, Yamamoto Koichi
Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Hypertens Res. 2025 Jun 18. doi: 10.1038/s41440-025-02261-5.
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.
我们之前报道过，氧化型低密度脂蛋白（oxLDL）通过凝集素样oxLDL受体（LOX-1）-1型血管紧张素II（AII）受体（AT1）复合物激活AT1。虽然单独的oxLDL不会激活G蛋白αq（Gq），但其与AII同时结合会改变AT1结构，增强Gq激活。我们研究了这种相互作用对肾上腺醛固酮生成的影响。用人肾上腺细胞（H295R）分别用赋形剂、oxLDL、AII或oxLDL与AII的组合进行处理。使用肌醇单磷酸（IP1）测定评估Gq信号传导，使用Fura2测定Ca2+内流，并使用qRT-PCR测定醛固酮合成基因表达。在体内，给野生型（WT）和LOX-1基因敲除（KO）小鼠喂食正常饮食（ND）或高脂饮食（HFD）以提高oxLDL水平，随后皮下注射AII或生理盐水4周（长期）或3天（短期）。在H295R细胞中，单独的oxLDL不会诱导IP1产生；然而，oxLDL增强了AII诱导的IP1和Ca2+内流。这些作用被LOX-1 siRNA消除。oxLDL与AII共同给药上调了醛固酮合成基因，如CYP11B2；这种作用被Gq抑制剂抑制。在体内，长期给予AII和HFD会增加肾上腺CYP11B2表达，但不会增加血清醛固酮水平。相反，短期给予AII和oxLDL会升高血清醛固酮水平，但不会增加CYP11B2表达。这些作用在LOX-1 KO小鼠中不存在。在两种模型中，HFD或oxLDL对血压均无影响。总之，oxLDL通过LOX-1-AT1相互作用增强AII诱导的肾上腺醛固酮生成，尽管其对血压调节的影响仍不清楚。氧化型LDL通过肾上腺细胞中的AT1-LOX-1受体复合物增强血管紧张素II的Gq信号传导和醛固酮生成。LOX-1通过调节肾上腺中的AT1受体信号传导放大血管紧张素II诱导的醛固酮合成。oxLDL的共同刺激通过LOX-1-AT1相互作用增强Gq激活，可能是通过AT1独特的构象变化。这些发现强调了血脂异常与肾素-血管紧张素-醛固酮系统（RAAS）在促进高血压和心血管疾病中的相互作用。
