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 (AT(1)R). Hypoxia, cobalt chloride, and dimethyloxalylglycine, all known to inhibit PHD, reduced AT(1)R expression in vascular smooth muscle cells.
Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT(1)R expression.
Cobalt chloride diminished angiotensin II-induced extracellular signal-regulated kinase phosphorylation.
Cobalt chloride decreased AT(1)R 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 AT(1)R downregulation.
- Amino Acids, Dicarboxylic
- Angiotensin II
- Blood Pressure
- Blotting, Northern
- Blotting, Western
- Cell Hypoxia
- Cells, Cultured
- Hypoxia-Inducible Factor 1, alpha Subunit
- Mice, Inbred C57BL
- Muscle, Smooth, Vascular
- Myocytes, Smooth Muscle
- Procollagen-Proline Dioxygenase
- RNA Interference
- Rats, Sprague-Dawley
- Receptor, Angiotensin, Type 1
- Receptor, Angiotensin, Type 2
- Reverse Transcriptase Polymerase Chain Reaction
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
Hypertension. 2011 Sep;58(3):386-93
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