Abstract-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 ␣ 1 and  1 is controlled at the posttranscriptional 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 sGC␣ 1 and sGC 1 in genetic hypertension. The expression of HuR (and sGC␣ 1 and sGC 1 ) 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 3Ј-untranslated region of sGC␣ 1 and sGC 1 . 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 sGC␣ 1 and sGC 1 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. Key Words: rats, spontaneously hypertensive Ⅲ aorta Ⅲ gene regulation Ⅲ hypertension, genetic C hronic hypertension is associated with functional and morphological alterations of the vessel wall (ie, dysfunctional vascular endothelium and thickening of the smooth muscle layer). The pathomechanisms accounting for hypertension-induced vascular alterations are likely to be multifactorial. A major homeostatic factor in the vessel wall is NO, which is generated from L-arginine by endothelial NO synthase. NO reduces vascular tone by activation of soluble guanylyl cyclase (sGC) and stimulation of cGMP formation and cGMP-activated protein kinase-I (cGK-I). Activated cGK-I reduces vascular tone by interference with intracellular Ca 2ϩ mobilization 1 and inhibition of contractile filament function. 2 In animal models of hypertension such as the spontaneously hypertensive rat (SHR), disturbances of the NO-cGMP system contribute to vascular dysfunction. Thus, increased oxidative stress interfering with endogenous NO bioavailability and reduced expression of sGC interfering with NO downstream signaling have been reported. 3-5 sGC is a heterodimeric hemoprotein consisting of ␣ 1 (76 to 81.5 kDa) and  1 (70 kDa) subunits. 6 We have shown recently that the expression of sGC is subject to post-transcriptional regulation. 7 The elav-like (embryonic-le...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.