Genetics of NO Deficiency

Leineweber, Kirsten; Moosmang, Sven; Paulson, Dan

doi:10.1016/j.amjcard.2017.06.013

Cited by 17 publications

(15 citation statements)

References 64 publications

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“…There is growing evidence supporting the relationship between genetic variants in the NO/sGC/cGMP pathway, and the prevalence and progression of cardiovascular, pulmonary, and renal diseases (Leineweber et al 2017). Importantly, genetic alterations of the GUCY1A3 gene, which encodes the α1 subunit of the sGC, are associated with coronary artery disease as well as Moyamoya disease, achalasia, and hypertension (Erdmann et al 2013;Kessler et al 2017;Wallace et al 2016).…”

mentioning

confidence: 99%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

131

149

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When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.

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mentioning

confidence: 99%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

131

149

View full text Add to dashboard Cite

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“…The clinical data is supported by genetic association studies, which have implicated dysfunctions of the cGMP signaling cascade in hypertension, coronary artery disease, and myocardial infarction in humans [ 81 ]. Importantly, even subtle changes due to genetic variants in components of this pathway (e.g., NO-GC, ANP, BNP; PDEs) significantly influence blood pressure and cardiovascular disease risk [ 82 , 83 , 84 , 85 , 86 ].…”

Section: Cgmp and Vascular Diseasesmentioning

confidence: 99%

cGMP Signaling and Vascular Smooth Muscle Cell Plasticity

Lehners

Dobrowinski

Feil

et al. 2018

JCDD

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Cyclic GMP regulates multiple cell types and functions of the cardiovascular system. This review summarizes the effects of cGMP on the growth and survival of vascular smooth muscle cells (VSMCs), which display remarkable phenotypic plasticity during the development of vascular diseases, such as atherosclerosis. Recent studies have shown that VSMCs contribute to the development of atherosclerotic plaques by clonal expansion and transdifferentiation to macrophage-like cells. VSMCs express a variety of cGMP generators and effectors, including NO-sensitive guanylyl cyclase (NO-GC) and cGMP-dependent protein kinase type I (cGKI), respectively. According to the traditional view, cGMP inhibits VSMC proliferation, but this concept has been challenged by recent findings supporting a stimulatory effect of the NO-cGMP-cGKI axis on VSMC growth. Here, we summarize the relevant studies with a focus on VSMC growth regulation by the NO-cGMP-cGKI pathway in cultured VSMCs and mouse models of atherosclerosis, restenosis, and angiogenesis. We discuss potential reasons for inconsistent results, such as the use of genetic versus pharmacological approaches and primary versus subcultured cells. We also explore how modern methods for cGMP imaging and cell tracking could help to improve our understanding of cGMP’s role in vascular plasticity. We present a revised model proposing that cGMP promotes phenotypic switching of contractile VSMCs to VSMC-derived plaque cells in atherosclerotic lesions. Regulation of vascular remodeling by cGMP is not only an interesting new therapeutic strategy, but could also result in side effects of clinically used cGMP-elevating drugs.

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“…ADMA e L-NMMA reduzem a síntese de NO por inibir tanto a enzima óxido nítrico sintase diretamente quanto a captação celular de L-arginina pelos transportadores de aminoácidos catiônicos (CAT) [46]. A degradação dessas substâncias é catalisada pela enzima dimetil arginina dimetilamina hidrolase (DDAH), que existe em duas isoformas em humanos: DDAH1 e DDAH2 [47]. Já SDMA atua apenas inibindo a captação celular de L-arginina pelos CATs, não sendo capaz de inibir diretamente a atividade das óxido nítrico sintases [46].…”

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“…Em mamíferos, foram identificadas duas isoformas de arginases: arginase 1 (ARG1), localizada no citosol, predominantemente nos hepatócitos, e arginase 2 (ARG2), presente nas mitocôndrias em diversos tecidos, dentre eles, os corpos cavernosos [47,[53][54][55]. Ambas isoformas estão presentes no endotélio vascular [47,53,54].…”

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Influência do tratamento de comorbidades sobre o sucesso da terapia da disfunção erétil: foco na via do óxido nítrico

Pereira¹

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Aos meus pais, por me apoiarem em tudo sempre, por estarem sempre comigo, mesmo que à distância, e por me amarem incondicionalmente. Às minhas madrinhas e meu padrinho, Nara, Rita e Angelo, por serem meus segundos pais e sempre me apoiarem e se preocuparem comigo. Ao meu noivo, Del, pelo apoio, amor e companhia durante essa jornada.Ao meu orientador, Prof. Dr. Riccardo Lacchini, por me aceitar em seu grupo de pesquisa desde minha iniciação científica, pelos ensinamentos e pelas oportunidades. Aos meus colegas de laboratório, Aline, Anderson, Cezar, Fernanda, Leevan e Sherliane, e, especialmente, Ana e Letícia, por toda a ajuda durante a elaboração deste trabalho e amizade. À colaboradora dra. Fernanda Lacchini, por toda a ajuda durante o desenvolvimento deste projeto. Ao colaborador dr. Lucas Cezar Pinheiro, pela ajuda na elaboração deste trabalho. Aos membros da banca de qualificação, pelas contribuições neste trabalho.Ao Prof. Dr. José Eduardo Tanus dos Santos, por fornecer gentilmente materiais e equipamentos necessários para realização deste trabalho, e aos membros do seu grupo de pesquisa, por toda ajuda sempre que preciso. À Prof. Dra. Vera Lanchote, por aceitar essa colaboração e me receber de braços abertos em seu laboratório. Às doutoras Adriana e Maria Paula, por todos os ensinamentos e ajuda desde o início do projeto. Aos colegas do PKClin, Glauco, Igor, Leandro e Marta, e, especialmente, Fernanda, Jhohann e Tálita, por todas as lições, ajuda, companhia e amizade.

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Genetics of NO Deficiency

Cited by 17 publications

References 64 publications

Soluble Guanylate Cyclase Stimulators and Activators

Soluble Guanylate Cyclase Stimulators and Activators

cGMP Signaling and Vascular Smooth Muscle Cell Plasticity

Influência do tratamento de comorbidades sobre o sucesso da terapia da disfunção erétil: foco na via do óxido nítrico

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