Aldosterone regulates vascular gene transcription via oxidative stress-dependent and -independent pathways.
Aldosterone regulates vascular gene transcription via oxidative stress-dependent and -independent pathways.
复制标题
DOI：
10.1161/atvbaha.111.229070
复制
发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Jaffe IZ
中科院分区：
文献类型：
--
作者：
Newfell BG;Iyer LK;Mohammad NN;McGraw AP;Ehsan A;Rosano G;Huang PL;Mendelsohn ME;Jaffe IZ
醛固酮（Aldo）拮抗剂通过不清楚的机制预防心血管死亡。Aldo与盐皮质激素受体（MR）结合，MR是一种配体激活的转录因子，在人血管细胞中表达。在这里，我们定义了早期醛调节血管转录组，并研究了血管系统中可能导致血管疾病的基因调控机制。基因表达谱的Aldo处理的小鼠睾丸鉴定了72个基因调节的Aldo。这些基因在涉及血管功能和疾病的基因本体论类别中被过度代表。采用QRT-PCR方法验证并进一步探讨Aldo对血管基因的调控机制。醛调节血管基因表达抑制放线菌素D和MR拮抗剂支持转录MR依赖性机制。在血管内皮剥脱的情况下，Aldo对一组基因的调节得到增强，并被自由基清除剂Tempol阻断，这支持了Aldo与氧化应激依赖性血管损伤之间的协同作用。在主动脉弓，一个易患动脉粥样硬化的区域，与降主动脉相比，损伤增强的基因也表现出增强的表达，无论是在基线还是在Aldo暴露后。此外，临床上有益的MR拮抗剂螺内酯抑制了动脉粥样硬化患者主动脉组织中已鉴定基因的表达。本研究定义了醛调节的血管转录组，并表征了在血管损伤和易患动脉粥样硬化的区域中具有增强的醛刺激的氧化应激依赖性表达的促动脉粥样硬化基因的子集。抑制这些基因的MR调节可能在Aldo拮抗剂对血管疾病患者的保护作用中发挥作用，这些途径可能为预防人类动脉粥样硬化提供新的药物靶点。
Aldosterone (Aldo) antagonism prevents cardiovascular mortality by unclear mechanisms. Aldo binds to the mineralocorticoid receptor (MR), a ligand-activated transcription factor, which is expressed in human vascular cells. Here we define the early Aldo-regulated vascular transcriptome and investigate the mechanisms of gene regulation by Aldo in the vasculature that may contribute to vascular disease. Gene expression profiling of Aldo-treated mouse aortas identified 72 genes regulated by Aldo. These genes are overrepresented in Gene Ontology categories involved in vascular function and disease. QRT-PCR was used to confirm and further explore mechanisms of vascular gene regulation by Aldo. Aldo-regulated vascular gene expression was inhibited by actinomycin-D and MR antagonists supporting a transcriptional MR-dependent mechanism. Aldo regulation of a subset of genes was enhanced in the setting of vascular endothelial denudation and blocked by the free radical scavenger Tempol, supporting synergy between Aldo and vascular injury that is oxidative stress-dependent. In the aortic arch, a region predisposed to atherosclerosis, the injury-enhanced genes also demonstrated enhanced expression compared to the descending aorta, both at baseline and after Aldo exposure. Furthermore, the clinically beneficial MR antagonist spironolactone inhibited expression of the identified genes in aortic tissue from humans with atherosclerosis. This study defines the Aldo-regulated vascular transcriptome and characterizes a subset of proatherogenic genes with enhanced Aldo-stimulated, oxidative stress-dependent expression in the setting of vascular injury and in areas predisposed to atherosclerosis. Inhibition of MR regulation of these genes may play a role in the protective effects of Aldo antagonists in patients with vascular disease and these pathways may provide novel drug targets to prevent atherosclerosis in humans.