Crosstalk Between Glycoxidative Modification of Low-Density Lipoprotein, Angiotensin II-Sensitization, and Adrenocortical Aldosterone Release
Crosstalk Between Glycoxidative Modification of Low-Density Lipoprotein, Angiotensin II-Sensitization, and Adrenocortical Aldosterone Release
复制标题
低密度脂蛋白的糖氧化修饰、血管紧张素 II 敏化和肾上腺皮质醛固酮释放之间的串扰
DOI：
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发表时间：
2015
影响因子：
2.2
通讯作者：
S. Kopprasch
中科院分区：
文献类型：
--
作者：
S. Saha;Stefan R. Bornstein;J. Graessler;S. Kopprasch
摘要低密度脂蛋白（LDL）被认为是动脉粥样硬化的危险因素。在高血糖症的存在下，LDL经历糖氧化修饰，并且这种糖氧化（glycox）LDL促进2型糖尿病（T2 D）个体中的动脉粥样硬化。此外，由于其胆固醇含量，LDL有助于醛固酮生物合成，其由血管紧张素II（AngII）调节，并且与T2 D的心血管并发症有关。然而，glycoxLDL，AngII和醛固酮之间的串扰的分子机制尚未解释清楚。因此，本研究旨在研究体外修饰的glycoxLDL对AngII致敏的肾上腺皮质癌细胞系（NCI H295 R）中醛固酮释放的影响。通过连续密度梯度超离心从健康志愿者中分离的天然LDL（natLDL）在37 ℃下接受d-葡萄糖（200 mmol/l）6天的糖氧化修饰。用natLDL和glycoxLDL处理AngII致敏的H295 R细胞24 h，并将上清液用于醛固酮测定。处理的细胞用于蛋白质分离和mRNA定量。与natLDL相比，glycoxLDL对AngII致敏细胞的醛固酮释放产生显著更大的影响。用特定的药理学抑制剂治疗表明，修饰的LDL招募ERK 1/2和janus激酶-2对醛固酮合成酶进行转录调节。此外，glycoxLDL通过cAMP依赖性蛋白激酶A（PKA）途径调节醛固酮释放。然而，glycoxLDL诱导ERK磷酸化独立于PKA活化，这种新的机制可以作为治疗试验的靶点。总之，这项体外研究强调了LDL糖氧化修饰、AngII致敏和肾上腺皮质类固醇激素释放之间可能的因果关系。
Abstract Low-density lipoprotein (LDL) is considered to be a risk factor for atherosclerosis. In the presence of hyperglycemia, LDL undergoes glycoxidative modification and this glycoxidized (glycox) LDL promotes atherosclerosis in type 2 diabetic (T2D) individuals. Moreover, because of its cholesterol content, LDL contributes to aldosterone biosynthesis, which is modulated by angiotensin II (AngII) and has been implicated in cardiovascular complications of T2D. However, the molecular mechanism of the crosstalk between glycoxLDL, AngII, and aldosterone has not been explained clearly. Therefore, this study has been aimed to investigate the impact of in vitro modified glycoxLDL on aldosterone release in an AngII-sensitized adrenocortical carcinoma cell line (NCI H295R). Native LDL (natLDL), isolated from healthy volunteers by sequential density gradient ultracentrifugation, was subjected to d-glucose (200 mmol/l), for glycoxidative modification, at 37°C for 6 days. The AngII-sensitized H295R cells were treated with natLDL and glycoxLDL for 24 h and the supernatant was used for aldosterone measurement. The treated cells were utilized for protein isolation and mRNA quantification. Compared to natLDL, glycoxLDL produced a significantly greater effect on aldosterone release from AngII-sensitized cells. The treatment with specific pharmacological inhibitors suggests that modified LDL recruits ERK1/2 and janus kinase-2 for transcriptional regulation of aldosterone synthase. Moreover, glycoxLDL modulates aldosterone release via cAMP-dependent protein kinase A (PKA) pathway. However, glycoxLDL induces ERK phosphorylation independent of PKA activation and this novel mechanism could be targeted for therapeutic trials. In conclusion, this in vitro study emphasizes a possible causal relationship between LDL glycoxidative modification, AngII-sensitization, and adrenocortical steroid hormone release.
DOI：
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发表时间：
2002
期刊：
The Journal of biological chemistry
影响因子：
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作者：
J. Schmitt;P. Stork
通讯作者：
J. Schmitt;P. Stork
影响因子：
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作者：
J. Richards
通讯作者：
J. Richards
人类胎儿肾上腺对脂蛋白的利用和胆固醇的合成。
影响因子：
20.3
作者：
Carr,BR;Simpson,ER
通讯作者：
Simpson,ER