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1.
Nat Commun ; 6: 8482, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26442659

RESUMO

Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators.


Assuntos
Sistema Cardiovascular/metabolismo , Guanilato Ciclase/genética , Heme/genética , Músculo Liso Vascular/metabolismo , Óxido Nítrico/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Animais , Benzoatos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Técnicas de Introdução de Genes , Hipertensão/genética , Hipotensão/induzido quimicamente , Hipotensão/genética , Camundongos , Camundongos Transgênicos , Músculo Liso Vascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Guanilil Ciclase Solúvel , Fator de Necrose Tumoral alfa/farmacologia
2.
Circ Cardiovasc Genet ; 7(6): 920-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25373139

RESUMO

BACKGROUND: Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. High-altitude residents who do not develop pulmonary hypertension may host protective gene mutations. METHODS AND RESULTS: Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUCY1A3 in 3 subjects with a normal mean pulmonary artery pressure encodes an α1-A680T soluble guanylate cyclase (sGC) variant. Expression of the α1-A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified α1-A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro. CONCLUSIONS: The α1-A680T sGC variant may contribute to protection against high-altitude pulmonary hypertension and supports sGC as a pharmacological target for reducing pulmonary artery pressure in humans at altitude.


Assuntos
Doença da Altitude/genética , Guanilato Ciclase/genética , Hipertensão Pulmonar/genética , Receptores Citoplasmáticos e Nucleares/genética , Alelos , Doença da Altitude/patologia , Sequência de Aminoácidos , Animais , GMP Cíclico/metabolismo , Feminino , Genótipo , Guanilato Ciclase/metabolismo , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipertensão Pulmonar/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Óxido Nítrico/metabolismo , Filogenia , Polimorfismo de Nucleotídeo Único , Receptores Citoplasmáticos e Nucleares/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA , Transdução de Sinais , Guanilil Ciclase Solúvel
3.
PLoS One ; 6(7): e21853, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21789188

RESUMO

BACKGROUND: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension. METHODS AND RESULTS: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1. CONCLUSIONS: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.


Assuntos
Guanilato Ciclase/metabolismo , Miocárdio/patologia , Especificidade de Órgãos , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/urina , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ecocardiografia , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Testes de Função Renal , Tamanho do Órgão/efeitos dos fármacos , Especificidade de Órgãos/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Dahl , Guanilil Ciclase Solúvel , Análise de Sobrevida , Sístole/efeitos dos fármacos
4.
J Hypertens ; 28(8): 1666-75, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20613628

RESUMO

OBJECTIVES: The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low-renin and high-renin rat models of hypertension. METHODS: The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). RESULTS: In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. CONCLUSION: We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage.


Assuntos
Guanilato Ciclase/metabolismo , Coração/efeitos dos fármacos , Hipertensão/prevenção & controle , Rim/efeitos dos fármacos , Óxido Nítrico/metabolismo , Renina/fisiologia , Animais , Animais Geneticamente Modificados , Anti-Hipertensivos/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Guanilato Ciclase/antagonistas & inibidores , Hipertensão/induzido quimicamente , Hipertensão/enzimologia , Rim/patologia , Longevidade/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miocárdio/patologia , NG-Nitroarginina Metil Éster/toxicidade , Nefrectomia , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/patologia , Nefrite Intersticial/prevenção & controle , Pirazóis/farmacologia , Pirimidinas/farmacologia , Coelhos , Ratos , Ratos Wistar , Renina/efeitos dos fármacos , Transdução de Sinais
5.
Circ Res ; 105(1): 33-41, 2009 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-19478201

RESUMO

Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and downregulation of its major intracellular receptor, the alphabeta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of the heme of sGC, as well as the responsiveness of sGC to NO. sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here, we show that oxidation-induced downregulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand BAY 58-2667 prevented sGC ubiquitination and stabilized both alpha and beta subunits. Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC.


Assuntos
Guanilato Ciclase/metabolismo , Heme/metabolismo , Óxido Nítrico/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Vasodilatadores/farmacologia , Vasos Sanguíneos , Linhagem Celular , GMP Cíclico/metabolismo , Humanos , Oxirredução , Guanilil Ciclase Solúvel , Ubiquitinação
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