Aldosterone regulates vascular gene transcription via oxidative stress-dependent and-independent pathways

Brenna G. Newfell, Lakshmanan K. Iyer, Najwa N. Mohammad, Adam P. McGraw, Afshin Ehsan, Giuseppe Rosano, Paul L. Huang, Michael E. Mendelsohn, Iris Z. Jaffe

Research output: Contribution to journalArticlepeer-review

Abstract

Objective-: 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. Methods and results-: 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. Quantitative reverse transcription-polymerase chain reaction 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 with 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. Conclusion-: 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.

Original languageEnglish
Pages (from-to)1871-1880
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number8
DOIs
Publication statusPublished - Aug 2011

Keywords

  • aldosterone
  • gene expression
  • mineralocorticoid receptor antagonists
  • vascular biology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Aldosterone regulates vascular gene transcription via oxidative stress-dependent and-independent pathways'. Together they form a unique fingerprint.

Cite this