RGS2 expression and aldosterone: renin ratio modulate response to drug therapy in hypertensive patients

Semplicini, Andrea; Strapazzon, Giacomo; Papparella, Italia; Sartori, Michelangelo; Realdi, Anna; Macchini, Luisa; Calò, Lorenzo A.; Ceolotto, Giulio

doi:10.1097/hjh.0b013e328339930f

Cited by 16 publications

(15 citation statements)

References 35 publications

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“…RGS2 is a relatively selective GTPase-activating protein for G q -family proteins (Heximer et al, 1997), which mediate phospholipase C and Ca 2ϩ signaling, including that of many vasoconstrictor agents such as norepinephrine, angiotensin II, and endothelin-1. Consequently, hypertension in RGS2(Ϫ/Ϫ) mice (Heximer et al, 2003;Takimoto et al, 2009) and in humans with low RGS2 expression levels (Yang et al, 2005;Bodenstein et al, 2007;Semplicini et al, 2010) might be attributable to increased GPCR-mediated vasoconstriction. RGS2 expression is increased in patients with Bartter's/Gitelman's syndrome, a disorder characterized by low blood pressure (Calò et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

Sjögren

Parra

Heath

et al. 2012

Molecular Pharmacology

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Regulator of G protein signaling 2 (RGS2), a G q -specific GTPase-activating protein, is strongly implicated in cardiovascular function. RGS2(Ϫ/Ϫ) mice are hypertensive and prone to heart failure, and several rare human mutations that accelerate RGS2 degradation have been identified among patients with hypertension. Therefore, pharmacological up-regulation of RGS2 protein levels might be beneficial. We used a ␤-galactosidase complementation method to screen several thousand compounds with known pharmacological functions for those that increased RGS2 protein levels. Several cardiotonic steroids (CTSs), including ouabain and digoxin, increased RGS2 but not RGS4 protein levels. CTSs increased RGS2 protein levels through a post-transcriptional mechanism, by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment, whereas protein levels were increased 2-to 3-fold. Na ϩ /K ϩ -ATPase was required for the increase in RGS2 protein levels, because the effect was lost in Na ϩ /K ϩ -ATPase-knockdown cells. Furthermore, we demonstrated that CTS-induced increases in RGS2 levels were functional and reduced receptor-stimulated, G qdependent, extracellular signal-regulated kinase phosphorylation. Finally, we showed that in vivo treatment with digoxin led to increased RGS2 protein levels in heart and kidney. CTSinduced increases in RGS2 protein levels and function might modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism might contribute to the beneficial actions of low-dose digoxin treatment in heart failure. Our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapy.

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Section: Introductionmentioning

confidence: 99%

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

Sjögren

Parra

Heath

et al. 2012

Molecular Pharmacology

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“…Such polymorphisms would not alter the RGS2 * This work was supported, in whole or in part, by National Institutes of Health protein sequence but might affect RGS2 mRNA and protein expression levels, and reductions in RGS2 expression have been observed in cells from hypertensive patients with RGS2 gene polymorphisms (10,12). In contrast, increased RGS2 expression has been observed in cells from hypotensive patients with Bartter/Gitelman syndrome (13).…”

mentioning

confidence: 99%

Identification of a cAMP-response Element in the Regulator of G-protein Signaling-2 (RGS2) Promoter as a Key Cis-regulatory Element for RGS2 Transcriptional Regulation by Angiotensin II in Cultured Vascular Smooth Muscles

Xie

Liu

et al. 2011

Journal of Biological Chemistry

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Background: Angiotensin II-induced regulator of G-protein signaling-2 (RGS2) expression is an important negative feedback loop in blood pressure homeostasis. Results: A conserved cAMP-response element-binding protein (CREB) binding site is found in the RGS2 promoter and is associated with three SNPs identified in hypertensive patients. Conclusion: CREB links the angiotensin II/PKC/iPLA 2 ␤/PKA signaling and RGS2 transcription. Significance: This study delineates a negative feedback loop with potential importance in the pathogenesis of human hypertension.

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“…This hypothesis originates from our recent findings (Semplicini et al, 2010) showing in a cohort of resistant hypertensives that:…”

Section: Disproportionate Aldosterone Secretion and Reduced Rgs2 Exprmentioning

confidence: 98%

“…In fact, resistant hypertensives were characterized by higher plasma aldosterone, ARR and reduced RGS2 expression in peripheral blood mononuclear cells in comparison to responder to antihypertensive drugs. (Semplicini et al, 2010).…”

Section: Clinical Hypertension and Rgs2 Deficiencymentioning

confidence: 99%

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Resistant Hypertension, Elevated Aldosterone/Renin Ratio and Reduced RGS2: A Pathogenetic Link Deserving Further Investigations?

Semplicini¹,

Stella²,

Ceolotto³

2012

Genetics and Pathophysiology of Essential Hypertension

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RGS2 expression and aldosterone: renin ratio modulate response to drug therapy in hypertensive patients

Abstract: RGS2 expression affects the response to antihypertensive treatment. Reduced RGS2 expression contributes to resistance to antihypertensive agents through poor negative feedback on the effects of aldosterone and of other vasoactive agents.

Cited by 16 publications

References 35 publications

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

Identification of a cAMP-response Element in the Regulator of G-protein Signaling-2 (RGS2) Promoter as a Key Cis-regulatory Element for RGS2 Transcriptional Regulation by Angiotensin II in Cultured Vascular Smooth Muscles

Resistant Hypertension, Elevated Aldosterone/Renin Ratio and Reduced RGS2: A Pathogenetic Link Deserving Further Investigations?

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