Inhibition of Prolyl Hydroxylase Domain-Containing Protein Downregulates Vascular Angiotensin II Type 1 Receptor

Abstract

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 (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. (Hypertension. 2011;58:386-393.) • Online Data Supplement Key Words: angiotensin II type 1 receptor Ⅲ renin angiotensin system Ⅲ prolyl hydroxylase domain-containing protein Ⅲ vascular remodeling R enin-angiotensin system (RAS) physiologically and pathophysiologically plays a pivotal role in the cardiovascular system. RAS modulates blood pressure, fluid and electrolyte homeostasis, and neuronal function. 1 RAS is also critical for the pathogenesis of cardiovascular diseases, such as hypertension, atherosclerosis, ischemic heart disease, and congestive heart failure. 2 Angiotensin II (Ang II), the primary active circulating component of the RAS, is a multifunctional hormone responsible for many cellular processes, such as inflammation, fibrosis, migration, proliferation, hypertrophy, and apoptosis, resulting in the cardiovascular remodeling. 3 The effects of Ang II are mediated by Ang II receptors, and 2 distinct isoforms of 7-transmembrane, G protein-coupled receptors have ever been cloned, Ang II type 1 receptor (AT 1 R) 4 and Ang II type 2 receptor. 5 It is generally accepted that AT 1 R mainly contributes to the progression of cardiovascular diseases. Indeed, many large-scale randomized clinical trials showed the beneficial effects of AT 1 R antagonists in the treatment of cardiovascular diseases. 6 Cardiovascular diseases are intimately related to the reduced oxygen concentration state (hypoxia). Cardiomyocytes in ischemic heart disease, peripheral organs in heart failure, ischemic limb in arteriosclerosis obliterans, and the brain in cerebral infarction are subject to hypoxia. Recently, it was reported that hypoxia activates both circulating and local RAS. 7,8 Hypoxia-inducible factor 1 (HIF-1) ...

The Role of Hypoxia-Inducible Factor/Prolyl Hydroxylation Pathway in Deoxycorticosterone Acetate/Salt Hypertension in the Rat

“…Similarly, PHD inhibition upregulated HIF-1α level and attenuated salt-induced hypertension in Dahl S rats, a salt-sensitive hypertensive model [4]. These and other studies showing that PHD inhibition downregulated vascular angiotensin type 1 receptor [9], support a protective role for increased HIF-1α expression and activity in CVDs. However, other studies documented the contrary: that hypoxia participates in the progression of CVDs.…”

Neovascularization induced by hypoxia inducible transcription factor is associated with the improvement of cardiac dysfunction in experimental autoimmune myocarditis

“…For example, inhibition of PHD2 could downregulate vascular angiotensin 2 type 1 receptors and reduce fibrosis [66]. In addition, HIF-PHD might possibly have cross-reactivity with collagen prolyl hydroxylase that belongs to the same 2-oxoglutarate-dependent oxygenase family and involves collagen deposition [67].…”

The activities of endothelial elastase and cathepsin G in rats at oxidative stress caused by heavy metals salts

“…Because of development of oxidative stress in the heart, as in the liver, it may be a release of cathepsin G by neutrophils [30], which is able to form vasoconstrictor peptide angiotensin II from angiotensin I and/or angiotensinogen [13,14]. CoCl 2 inhibits the reninangiotensin system by reducing the expression of angiotensin I in vascular smooth muscle cells [33]. Thus, we can assume the possibility of formation of angiotensin II from angiotensinogen with cathepsin G participation at the CoCl 2 action which contributes to the development of hypertensive changes.…”