Human-Antigen R (HuR) Expression in Hypertension: Downregulation of the mRNA Stabilizing Protein HuR in Genetic Hypertension

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2005-06, Vol.45 (6), p.1200-1206
• Main Authors: Klöss, Stephan, Rodenbach, Daniela, Bordel, Reingart, Mülsch, Alexander
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - metabolism; Aging - metabolism; Animals; Antigens, Surface - genetics; Antigens, Surface - metabolism; Aorta - chemistry; Aorta - metabolism; Chronic Disease; Down-Regulation; ELAV Proteins; ELAV-Like Protein 1; Electrophoresis; Guanylate Cyclase - chemistry; Guanylate Cyclase - genetics; Guanylate Cyclase - metabolism; Hypertension - genetics; Hypertension - metabolism; In Vitro Techniques; Male; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recombinant Proteins - metabolism; RNA Stability - drug effects; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Solubility; Tissue Extracts - pharmacology
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/01.HYP.0000165674.58470.8f

In aged spontaneously hypertensive rats (SHR), vasorelaxant responses to NO are attenuated compared with normotensive control rats (Wistar-Kyoto [WKY]) because of a decreased expression of the important NO receptor soluble guanylyl cyclase (sGC). Because the expression of sGC subunits α1 and β1 is controlled at the post-transcriptional level by the mRNA-binding protein human-antigen R (HuR), we now assessed whether or not altered expression of HuR could account for downregulation of sGCα1 and sGCβ1 in genetic hypertension. The expression of HuR (and sGCα1 and sGCβ1) in aortas from aged SHR was significantly decreased at the mRNA and protein level compared with age-matched WKY rats, whereas expression of HuR was not different in prehypertensive young (2 months of age) SHR and age-matched WKY rats. The mRNA-binding activity of HuR in native aortic protein extracts from aged SHR was markedly reduced compared with normotensive WKY rats, as detected by RNA electrophoretic mobility shift analysis, using biotin-labeled adenine and uracil (AU)–rich element (ARE)–containing RNA probes from the 3′-untranslated region of sGCα1 and sGCβ1. In contrast, ARE-binding activity was not different between prehypertensive young SHR and young WKY rats. In vitro RNA degradation assays using the same AU-rich sGC mRNA probes revealed an accelerated sGCα1 and sGCβ1 mRNA decay in the presence of native protein extract from hypertensive SHR, which was less rapid with aortic protein from normotensive WKY rats. These findings suggest that in this animal model of genetic hypertension, the reduced expression of sGC subunits is mediated by downregulation of the sGC mRNA–stabilizing protein HuR.