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1.
Circ Res ; 132(4): 400-414, 2023 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-36715019

RESUMO

BACKGROUND: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways. METHODS: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes. RESULTS: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in ICaL, INaL, and Ca2+ spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca2+ handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. CONCLUSIONS: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies.


Assuntos
Miócitos Cardíacos , Diester Fosfórico Hidrolases , Camundongos , Animais , Humanos , Diester Fosfórico Hidrolases/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Catecolaminas/metabolismo , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/prevenção & controle , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiarrítmicos/metabolismo , GMP Cíclico/metabolismo , Peptídeo Natriurético Tipo C/farmacologia
2.
Circ Res ; 129(8): 804-820, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34433292
3.
Int J Mol Sci ; 22(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062838

RESUMO

BACKGROUND: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to ß-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. METHODS: Cellular arrhythmia, ion currents, and Ca2+-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. RESULTS: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in ICaL seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in INaL and Ca2+-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. CONCLUSION: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.


Assuntos
Arritmias Cardíacas/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Antiarrítmicos/farmacologia , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/patologia , Cálcio/metabolismo , AMP Cíclico/genética , GMP Cíclico/genética , Regulação da Expressão Gênica/genética , Coração/fisiopatologia , Humanos , Isoproterenol/toxicidade , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo
4.
Int J Mol Sci ; 21(20)2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33050419

RESUMO

Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3',5'-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is often perceived under pathological conditions. Thereby PDEs have long been pursued as therapeutic targets in diverse disease conditions including neurological, metabolic, cancer and autoimmune disorders in addition to numerous cardiovascular diseases (CVDs). PDE2 is a unique member of the broad family of PDEs. In addition to its capability to hydrolyze both cAMP and cGMP, PDE2 is the sole isoform that may be allosterically activated by cGMP increasing its cAMP hydrolyzing activity. Within the cardiovascular system, PDE2 serves as an integral regulator for the crosstalk between cAMP/cGMP pathways and thereby may couple chronically adverse augmented cAMP signaling with cardioprotective cGMP signaling. This review provides a comprehensive overview of PDE2 regulatory functions in multiple cellular components within the cardiovascular system and also within various subcellular microdomains. Implications for PDE2- mediated crosstalk mechanisms in diverse cardiovascular pathologies are discussed highlighting the prospective use of PDE2 as a potential therapeutic target in cardiovascular disorders.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Transdução de Sinais , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Sistema Cardiovascular/metabolismo , Fibroblastos , Humanos , Miócitos Cardíacos/metabolismo , Neurônios , Óxido Nítrico/metabolismo , Sistemas do Segundo Mensageiro
5.
Bioorg Chem ; 85: 349-356, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30658234

RESUMO

A series of dimeric melatonin analogues 3a-e obtained by connecting two melatonin molecules through the methoxy oxygen atoms with spacers spanning 16-24 atoms and the agomelatine dimer 7 were synthesized and characterized in 2-[125-I]-iodomelatonin binding assays, bioluminescence resonance energy transfer (BRET) experiments, and in functional cAMP and ß-arrestin recruitment assays at MT1 and MT2 receptors. The binding affinity of 3a-e generally increased with increasing linker length. Bivalent ligands 3a-e increased BRET signals of MT1 dimers up to 3-fold compared to the monomeric control ligand indicating the simultaneous binding of the two pharmacophores to dimeric receptors. Bivalent ligands 3c and 7 exhibited important changes in functional properties on the Gi/cAMP pathway but not on the ß-arrestin pathway compared to their monomeric counterparts. Interestingly, 3c (20 atoms spacer) shows inverse agonistic properties at MT2 on the Gi/cAMP pathway. In conclusion, these findings indicate that O-linked melatonin dimers are promising tools to develop signaling pathway-based bivalent melatonin receptor ligands.


Assuntos
Melatonina/análogos & derivados , Melatonina/farmacologia , Receptor MT1 de Melatonina/agonistas , Receptor MT2 de Melatonina/agonistas , Técnicas de Transferência de Energia por Ressonância de Bioluminescência , AMP Cíclico/metabolismo , Agonismo Inverso de Drogas , Células HEK293 , Humanos , Ligantes , Melatonina/metabolismo , Estrutura Molecular , Multimerização Proteica/efeitos dos fármacos , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , beta-Arrestinas/metabolismo
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