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1.
Br J Pharmacol ; 179(11): 2443-2459, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34131904

RESUMO

BACKGROUND AND PURPOSE: cGMP underpins the bioactivity of NO and natriuretic peptides and is key to cardiovascular homeostasis. cGMP-driven responses are terminated primarily by PDEs, but cellular efflux via multidrug resistance proteins (MRPs) might contribute. Herein, the effect of pharmacological blockade of MRPs on cGMP signalling in the heart and vasculature was investigated in vitro and in vivo. EXPERIMENTAL APPROACH: Proliferation of human coronary artery smooth muscle cells (hCASMCs), vasorelaxation of murine aorta and reductions in mean arterial BP (MABP) in response to NO donors or natriuretic peptides were determined in the absence and presence of the MRP inhibitor MK571. The ability of MRP inhibition to reverse morphological and contractile deficits in a murine model of pressure overload-induced heart failure was also explored. KEY RESULTS: MK571 attenuated hCASMC growth and enhanced the anti-proliferative effects of NO and atrial natriuretic peptide (ANP). MRP blockade caused concentration-dependent relaxations of murine aorta and augmented responses to ANP (and to a lesser extent NO). MK571 did not decrease MABP per se but enhanced the hypotensive actions of ANP and improved structural and functional indices of disease severity in experimental heart failure. These beneficial actions of MRP inhibition were associated with a greater intracellular:extracellular cGMP ratio in vitro and in vivo. CONCLUSIONS AND IMPLICATIONS: MRP blockade promotes the cardiovascular functions of natriuretic peptides in vitro and in vivo, with more modest effects on NO. MRP inhibition may have therapeutic utility in cardiovascular diseases triggered by dysfunctional cGMP signalling, particularly those associated with altered natriuretic peptide bioactivity. LINKED ARTICLES: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.


Assuntos
Fator Natriurético Atrial , Insuficiência Cardíaca , Subfamília B de Transportador de Cassetes de Ligação de ATP , Animais , Fator Natriurético Atrial/metabolismo , Fator Natriurético Atrial/farmacologia , GMP Cíclico/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Camundongos , Peptídeos Natriuréticos/metabolismo , Vasodilatadores
2.
Cardiovasc Drugs Ther ; 34(3): 401-417, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32172427

RESUMO

The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) maintain physiological cardiac contractility and integrity. Cyclic nucleotide-hydrolysing phosphodiesterases (PDEs) are the prime regulators of cAMP and cGMP signalling in the heart. During heart failure (HF), the expression and activity of multiple PDEs are altered, which disrupt cyclic nucleotide levels and promote cardiac dysfunction. Given that the morbidity and mortality associated with HF are extremely high, novel therapies are urgently needed. Herein, the role of PDEs in HF pathophysiology and their therapeutic potential is reviewed. Attention is given to PDEs 1-5, and other PDEs are briefly considered. After assessing the role of each PDE in cardiac physiology, the evidence from pre-clinical models and patients that altered PDE signalling contributes to the HF phenotype is examined. The potential of pharmacologically harnessing PDEs for therapeutic gain is considered.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/metabolismo , Animais , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Miócitos Cardíacos/enzimologia , Transdução de Sinais
3.
J Cardiovasc Pharmacol ; 75(5): 370-384, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31498237

RESUMO

Heart failure (HF) is a common consequence of several cardiovascular diseases and is understood as a vicious cycle of cardiac and hemodynamic decline. The current inventory of treatments either alleviates the pathophysiological features (eg, cardiac dysfunction, neurohumoral activation, and ventricular remodeling) and/or targets any underlying pathologies (eg, hypertension and myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine-3',5'-monophosphate (cGMP), synthesized by nitric oxide (NO)- and natriuretic peptide (NP)-responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signaling, which can occur after GC deactivation and the upregulation of cyclic nucleotide-hydrolyzing phosphodiesterases (PDEs), promotes cardiac dysfunction. In this study, we review the role that NO/cGMP and NP/cGMP signaling plays in HF. After considering disease etiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from preclinical models and patients that compromised cGMP signaling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined.


Assuntos
GMP Cíclico/metabolismo , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Peptídeos Natriuréticos/metabolismo , Óxido Nítrico/metabolismo , Sistemas do Segundo Mensageiro , Animais , Fármacos Cardiovasculares/uso terapêutico , Guanilato Ciclase/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Terapia de Alvo Molecular , Contração Miocárdica , Diester Fosfórico Hidrolases/metabolismo , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Função Ventricular Esquerda , Remodelação Ventricular
4.
Proc Natl Acad Sci U S A ; 115(31): E7428-E7437, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30012589

RESUMO

Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3',5'-monophosphate (cGMP) signaling, underpinned, in part, by up-regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well-defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1α (GC-1α-/-) or natriuretic peptide-responsive GC-A (GC-A-/-), we demonstrate that the blockade of PDE2 promotes cGMP signaling to offset the pathogenesis of experimental HF (induced by pressure overload or sympathetic hyperactivation), reversing the development of left ventricular hypertrophy, compromised contractility, and cardiac fibrosis. Moreover, we show that this beneficial pharmacodynamic profile is maintained in GC-A-/- mice but is absent in animals null for GC-1α or treated with a NO synthase inhibitor, revealing that PDE2 inhibition preferentially enhances NO/GC/cGMP signaling in the setting of HF to exert wide-ranging protection to preserve cardiac structure and function. These data substantiate the targeting of PDE2 in HF as a tangible approach to maximize myocardial cGMP signaling and enhancing therapy.


Assuntos
GMP Cíclico/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/fisiologia , Guanilato Ciclase/fisiologia , Insuficiência Cardíaca/tratamento farmacológico , Óxido Nítrico/fisiologia , Inibidores de Fosfodiesterase/farmacologia , Transdução de Sinais/fisiologia , Animais , Células Cultivadas , GMP Cíclico/análise , Masculino , Camundongos
5.
Dis Model Mech ; 8(9): 1105-19, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26159543

RESUMO

Anti-angiogenic treatments against αvß3-integrin fail to block tumour growth in the long term, which suggests that the tumour vasculature escapes from angiogenesis inhibition through αvß3-integrin-independent mechanisms. Here, we show that suppression of ß3-integrin in mice leads to the activation of a neuropilin-1 (NRP1)-dependent cell migration pathway in endothelial cells via a mechanism that depends on NRP1's mobilisation away from mature focal adhesions following VEGF-stimulation. The simultaneous genetic targeting of both molecules significantly impairs paxillin-1 activation and focal adhesion remodelling in endothelial cells, and therefore inhibits tumour angiogenesis and the growth of already established tumours. These findings provide a firm foundation for testing drugs against these molecules in combination to treat patients with advanced cancers.


Assuntos
Adesões Focais , Integrina beta3/metabolismo , Integrinas/antagonistas & inibidores , Neovascularização Patológica , Neuropilina-1/metabolismo , Animais , Adesão Celular , Citoplasma , Citoesqueleto/metabolismo , Células Endoteliais/citologia , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Heterozigoto , Humanos , Pulmão/fisiopatologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microcirculação , Transplante de Neoplasias , Paxilina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
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