Inhibition of prolyl hydroxylase domain-containing protein downregulates vascular angiotensin II type 1 receptor

Hirohide Matsuura, Toshihiro Ichiki, Jiro Ikeda, Kotaro Takeda, Ryohei Miyazaki, Toru Hashimoto, Eriko Narabayashi, Shiro Kitamoto, Tomotake Tokunou, Kenji Sunagawa

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Inhibition of prolyl hydroxylase domain-containing protein (PHD) by hypoxia stabilizes hypoxia-inducible factor 1 and increases the expression of target genes, such as vascular endothelial growth factor. Although the systemic renin-angiotensin system is activated by hypoxia, the role of PHD in the regulation of the renin-angiotensin system remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin II type 1 receptor (AT1R). Hypoxia, cobalt chloride, and dimethyloxalylglycine, all known to inhibit PHD, reduced AT1R expression in vascular smooth muscle cells. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT1R expression. Cobalt chloride diminished angiotensin II-induced extracellular signal-regulated kinase phosphorylation. Cobalt chloride decreased AT1R mRNA through transcriptional and posttranscriptional mechanisms. Oral administration of cobalt chloride (14 mg/kg per day) to C57BL/6J mice receiving angiotensin II infusion (490 ng/kg per minute) for 4 weeks significantly attenuated perivascular fibrosis of the coronary arteries without affecting blood pressure level. These data suggest that PHD inhibition may be beneficial for the treatment of cardiovascular diseases by inhibiting renin-angiotensin system via AT1R downregulation.

Original languageEnglish
Pages (from-to)386-393
Number of pages8
JournalHypertension
Volume58
Issue number3
DOIs
Publication statusPublished - Sep 2011

All Science Journal Classification (ASJC) codes

  • Internal Medicine

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