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1.
Gen Comp Endocrinol ; 240: 1-9, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27633326

RESUMO

Chromogranin A (CgA) is an acidic protein co-stored with catecholamines, hormones and neuropeptides in the secretory granules of endocrine, neuronal and other cell types (including cardiomyocytes). Proteolytic cleavage in the C terminus of CgA generates a 2.9kDa peptide named serpinin (Serp; Ala26Leu) that can be modified at its N terminus to form a pyroglutamate residue (pGlu-Serp). In the rat heart, both peptides increase contractility and relaxation through a ß-adrenergic-like action mechanism. Accordingly, Serp and pGlu-Serp were proposed as novel myocardial sympatho-adrenergic modulators in mammals. On a comparative basis, here we report the actions of Serp and pGlu-Serp on myocardial contractility in three poikilotherm vertebrate species: the eel (Anguilla anguilla), the goldfish (Carassius auratus) and the frog (Rana esculenta). Using isolated working heart preparations, we show that pGlu-Serp reduces stroke volume in all species tested, while Serp reduces contractility in the frog heart, but is uneffective in eel and goldfish hearts. In the goldfish and frog hearts, pGlu-Serp activates the Nitric Oxide/cGMP pathway involving Endothelin-1 B receptors (frog) and ß3 adrenergic receptors (goldfish). pGlu-Serp-treated hearts from goldfish and frog show increased cGMP content. Moreover, the exposure of the frog heart to pGlu-Serp is accompanied by an increased expression of activated eNOS and Akt. In conclusion, this first report showing that pGlu-Serp inhibits mechanical cardiac performance in teleost and amphibians supports an evolutionary role of the CgA system, and particularly its serpinin component, in the sympatho-adrenergic control of the vertebrate heart.


Assuntos
Anfíbios/metabolismo , Cromogranina A/genética , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Simpatomiméticos/metabolismo , Animais , Fragmentos de Peptídeos/metabolismo , Transdução de Sinais
2.
Nutr Metab Cardiovasc Dis ; 26(7): 603-613, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27113292

RESUMO

BACKGROUND AND AIMS: Obesity is often associated with an increased cardiovascular risk. The food industry and the associated research activities focus on formulating products that are a perfect mix between an adequate fat content and health. We evaluated whether a diet enriched with Bio-Oil Spread (SD), an olive oil-based innovative food, is cardioprotective in the presence of high-fat diet (HFD)-dependent obesity. METHODS AND RESULTS: Rats were fed for 16 weeks with normolipidic diet (ND; fat: 6.2%), HFD (fat: 42%), and ND enriched with SD (6.2% of fat + 35.8% of SD). Metabolic and anthropometric parameters were measured. Heart and liver structures were analyzed by histochemical examination. Ischemic susceptibility was evaluated on isolated and Langendorff-perfused cardiac preparations. Signaling was assessed by Western blotting. Compared to ND rats, HFD rats showed increased body weight and abdominal obesity, dyslipidemia, and impaired glucose tolerance. Morphological analyses showed that HFD is associated with heart and liver modifications (hypertrophy and steatosis, respectively), lesser evident in the SD group, together with metabolic and anthropometric alterations. In particular, IGF-1R immunodetection revealed a reduction of hypertrophy in SD heart sections. Notably, SD diet significantly reduced myocardial susceptibility against ischemia/reperfusion (I/R) with respect to HFD through the activation of survival signals (Akt, ERK1/2, and Bcl2). Systolic and diastolic performance was preserved in the SD group. CONCLUSIONS: We suggest that SD may contribute to the prevention of metabolic disorders and cardiovascular alterations typical of severe obesity induced by an HFD, including the increased ischemic susceptibility of the myocardium. Our results pave the way to evaluate the introduction of SD in human alimentary guidelines as a strategy to reduce saturated fat intake.


Assuntos
Suplementos Nutricionais , Síndrome Metabólica/prevenção & controle , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Obesidade Abdominal/prevenção & controle , Azeite de Oliva/administração & dosagem , Gordura Abdominal/metabolismo , Gordura Abdominal/fisiopatologia , Adiposidade , Ração Animal , Animais , Apoptose , Biomarcadores/sangue , Glicemia/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/etiologia , Dislipidemias/prevenção & controle , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Intolerância à Glucose/sangue , Intolerância à Glucose/etiologia , Intolerância à Glucose/prevenção & controle , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Preparação de Coração Isolado , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Síndrome Metabólica/sangue , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade Abdominal/sangue , Obesidade Abdominal/etiologia , Obesidade Abdominal/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Função Ventricular Esquerda , Remodelação Ventricular
3.
Nitric Oxide ; 44: 71-80, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25499100

RESUMO

African lungfishes are obligate air breathers, with reduced gills and pulmonary breathing throughout their life. During the dry season they aestivate on land, with the collapse of secondary lamellae of their gills and the establishment of an exclusive aerial ventilation through the vascularization and expansion of their lungs. To date, the mechanisms underlining the respiratory organ remodeling in aestivating lungfishes are unknown. This study aimed to identify key switch components of the stress-induced signal transduction networks implicated in both rapid and medium-long term remodeling of the gills and lungs of the African lungfish Protopterus annectens during aestivation. Through immunofluorescence microscopy and Western blotting, the localization and the expression of nitric oxide synthase (NOS), Akt, Hsp-90 and HIF-1α were evaluated in both gills and lungs exposed to three experimental conditions: freshwater (FW), 6 months of experimentally induced aestivation (6mAe), and 6 days after arousal from 6 months of aestivation (6mAe6d). After 6mAe, the expression of NOS (p-eNOS antibody), Akt (p-Akt antibody), and Hsp-90 decreased in the gills, while NOS and Hsp-90 expression increased with Akt remained unchanged in the lungs. Upon 6mAe6d, NOS, Akt and Hsp-90 expression in the gills returned to the respective FW values. In the lungs of the aroused fish, NOS and Akt decreased to their respective FW levels, while Hsp-90 expression was enhanced with respect to aestivation. In both respiratory organs, the qualitative and quantitative patterns of HIF-1α expression correlated inversely to those of NOS. Overall, our findings suggest that the molecular components of the NOS/NO system changed in a tissue-specific manner in parallel with organ readjustment in the gills and lungs of P. annectens during aestivation and arousal.


Assuntos
Estivação/fisiologia , Brânquias/química , Pulmão/química , Óxido Nítrico Sintase/análise , Transdução de Sinais/fisiologia , Animais , Western Blotting , Peixes , Brânquias/metabolismo , Pulmão/metabolismo , Óxido Nítrico Sintase/metabolismo
4.
Nitric Oxide ; 50: 10-19, 2015 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-26241941

RESUMO

The myocardial response to mechanical stretch (Frank-Starling law) is an important physiological cardiac determinant. Modulated by many endogenous substances, it is impaired in the presence of cardiovascular pathologies and during senescence. Catestatin (CST:hCgA352-372), a 21-amino-acid derivate of Chromogranin A (CgA), displays hypotensive/vasodilatory properties and counteracts excessive systemic and/or intra-cardiac excitatory stimuli (e.g., catecholamines and endothelin-1). CST, produced also by the myocardium, affects the heart by modulating inotropy, lusitropy and the coronary tone through a Nitric Oxide (NO)-dependent mechanism. This study evaluated the putative influence elicited by CST on the Frank-Starling response of normotensive Wistar-Kyoto (WKY) and hypertensive (SHR) hearts by using isolated and Langendorff perfused cardiac preparations. Functional changes were evaluated on aged (18-month-old) WKY rats and SHR which mimic human chronic heart failure (HF). Comparison to WKY rats, SHR showed a reduced Frank-Starling response. In both rat strains, CST administration improved myocardial mechanical response to increased end-diastolic pressures. This effect was mediated by EE/IP3K/NOS/NO/cGMP/PKG, as revealed by specific inhibitors. CST-dependent positive Frank-Starling response is paralleled by an increment in protein S-Nitrosylation. Our data suggested CST as a NO-dependent physiological modulator of the stretch-induced intrinsic regulation of the heart. This may be of particular importance in the aged hypertrophic heart, whose function is impaired because of a reduced systolic performance accompanied by delayed relaxation and increased diastolic stiffness.

5.
Gen Comp Endocrinol ; 224: 160-7, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26248227

RESUMO

The hypothalamic neuropeptide Nesfatin-1 is present in both mammals and teleosts in which it elicits anorexigenic effects. In mammals, Nesfatin-1 acts on the heart by inducing negative inotropism and lusitropism, and cardioprotection against ischemic damages. We evaluated whether in teleosts, Nesfatin-1 also influences cardiac performance. In the goldfish (Carassius auratus), mature, fully processed Nesfatin-1 was detected in brain, gills, intestine and skeletal muscle, but not in the cardiac ventricle. However, on the isolated and perfused working goldfish heart, exogenous Nesfatin-1 induced a positive inotropic effect, revealed by a dose-dependent increase of stroke volume (SV) and stroke work (SW). Positive inotropism was abolished by inhibition of adenylate cyclase (AC; MDL123330A) and cAMP-dependent kinase (PKA; KT5720), suggesting a cAMP/PKA-mediated pathway. This was confirmed by the increased cAMP concentrations revealed by ELISA on Nesfatin-1-treated hearts. Perfusion with Diltiazem, Thapsigargin and PD98059 showed the involvement of L-type calcium channels, SERCA2a pumps and ERK1/2, respectively. The role of ERK1/2 and phospholamban in Nesfatin-1-induced cardiostimulation was supported by Western blotting analysis. In conclusion, this is the first report showing that in teleosts, Nesfatin-1 potentiates mechanical cardiac performance, strongly supporting the evolutionary importance of the peptide in the control of the cardiac function of vertebrates.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/farmacologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Proteínas de Ligação a DNA/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Coração/fisiologia , Proteínas do Tecido Nervoso/farmacologia , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Carpa Dourada , Coração/efeitos dos fármacos , Nucleobindinas
6.
Cell Mol Life Sci ; 70(3): 495-509, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22955491

RESUMO

Nesfatin-1 is an anorexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide. It controls feeding behavior, water intake, and glucose homeostasis. If intracerebrally administered, it induces hypertension, thus suggesting a role in central cardiovascular control. However, it is not known whether it is able to directly control heart performance. We aimed to verify the hypothesis that, as in the case of other hypothalamic satiety peptides, Nesfatin-1 acts as a peripheral cardiac modulator. By western blotting and QT-PCR, we identified the presence of both Nesfatin-1 protein and NUCB2 mRNA in rat cardiac extracts. On isolated and Langendorff-perfused rat heart preparations, we found that exogenous Nesfatin-1 depresses contractility and relaxation without affecting coronary motility. These effects did not involve Nitric oxide, but recruited the particulate guanylate cyclase (pGC) known as natriuretic peptide receptor A (NPR-A), protein kinase G (PKG) and extracellular signal-regulated kinases1/2 (ERK1/2). Co-immunoprecipitation and bioinformatic analyses supported an interaction between Nesfatin-1 and NPR-A. Lastly, we preliminarily observed, through post-conditioning experiments, that Nesfatin-1 protects against ischemia/reperfusion (I/R) injury by reducing infarct size, lactate dehydrogenase release, and postischemic contracture. This protection involves multiple prosurvival kinases such as PKCε, ERK1/2, signal transducer and activator of transcription 3, and mitochondrial K(ATP) channels. It also ameliorates contractility recovery. Our data indicate that: (1) the heart expresses Nesfatin-1, (2) Nesfatin-1 directly affects myocardial performance, possibly involving pGC-linked NPR-A, the pGC/PKG pathway, and ERK1/2, (3) the peptide protects the heart against I/R injury. Results pave the way to include Nesfatin-1 in the neuroendocrine modulators of the cardiac function, also encouraging the clarification of its clinical potential in the presence of nutrition-dependent physio-pathologic cardiovascular diseases.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Traumatismo por Reperfusão/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Ligação ao Cálcio/química , Proteínas de Ligação ao Cálcio/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Canais KATP/metabolismo , L-Lactato Desidrogenase/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Óxido Nítrico/metabolismo , Nucleobindinas , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores do Fator Natriurético Atrial/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais
7.
Nitric Oxide ; 32: 1-12, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23545405

RESUMO

African lungfishes (Protopterus spp.) are obligate air breathers which enter in a prolonged torpor (aestivation) in association with metabolic depression, and biochemical and morpho-functional readjustments during the dry season. During aestivation, the lungfish heart continues to pump, while the skeletal muscle stops to function but can immediately contract during arousal. Currently, nothing is known regarding the orchestration of the multilevel rearrangements occurring in myotomal and myocardial muscles during aestivation and arousal. Because of its universal role in cardio-circulatory and muscle homeostasis, nitric oxide (NO) could be involved in coordinating these stress-induced adaptations. Western blotting and immunofluorescence microscopy on cardiac and skeletal muscles of Protopterus annectens (freshwater, 6months of aestivation and 6days after arousal) showed that expression, localization and activity of the endothelial-like nitric oxide synthase (eNOS) isoform and its partners Akt and Hsp-90 are tissue-specifically modulated. During aestivation, phospho-eNOS/eNOS and phospho-Akt/Akt ratios increased in the heart but decreased in the skeletal muscle. By contrast, Hsp-90 increased in both muscle types during aestivation. TUNEL assay revealed that increased apoptosis occurred in the skeletal muscle of aestivating lungfish, but the myocardial apoptotic rate of the aestivating lungfish remained unchanged as compared with the freshwater control. Consistent with the preserved cardiac activity during aestivation, the expression of apoptosis repressor (ARC) also remained unchanged in the heart of aestivating and aroused fish as compared with the freshwater control. Contrarily, ARC expression was strongly reduced in the skeletal muscle of aestivating lungfish. On the whole, our data indicate that changes in the eNOS/NO system and cell turnover are implicated in the morpho-functional readjustments occurring in lungfish cardiac and skeletal muscle during the switch from freshwater to aestivation, and between the maintenance and arousal phases of aestivation.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Peixes/metabolismo , Músculo Esquelético/enzimologia , Miocárdio/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Apoptose/fisiologia , Estivação , Água Doce , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
8.
Nutr Metab Cardiovasc Dis ; 22(6): 486-94, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21186112

RESUMO

BACKGROUND AND AIMS: The anorexigenic glucagon-like peptide (GLP)-2 is produced by intestinal L cells and released in response to food intake. It affects intestinal function involving G-protein-coupled receptors. To verify whether GLP-2 acts as a cardiac modulator in mammals, we analysed, in the rat heart, the expression of GLP-2 receptors and the myocardial and coronary responses to GLP-2. METHODS AND RESULTS: GLP-2 receptors were detected on ventricular extracts by quantitative real-time polymerase chain reaction (Q-RT-PCR) and Western blotting. Cardiac GLP-2 effects were analysed on Langendorff perfused hearts. Intracellular GLP-2 signalling was investigated on Langendorff perfused hearts and by Western blotting and enzyme-linked immunosorbent assay (ELISA) on ventricular extracts. By immunoblotting and Q-RT-PCR, we revealed the expression of ventricular GLP-2 receptors. Perfusion analyses showed that GLP-2 induces positive inotropism at low concentration (10-12 mol l(-1)), and negative inotropism and lusitropism from 10 to 10 mol l(-1). It dose-dependently constricts coronaries. The negative effects of GLP-2 were independent from GLP-1 receptors, being unaffected by exendin-3 (9-39) amide. GLP-2-dependent negative action involves Gi/o proteins, associates with a reduction of intracellular cyclic adenosine monophosphate (cAMP), an increase in extracellular signal regulated kinases 1 and 2 (ERK1/2) and a decrease in phospholamban phosphorylation, but is independent from endothelial nitric oxide synthase (eNOS) and protein kinase G (PKG). Finally, GLP-2 competitively antagonised ß-adrenergic stimulation. CONCLUSIONS: For the first time, to our knowledge, we found that: (1) the rat heart expresses functional GLP-2 receptors; (2) GLP-2 acts on both myocardium and coronaries, negatively modulating both basal and ß-adrenergic stimulated cardiac performance; and (3) GLP-2 effects are mediated by G-proteins and involve ERK1/2.


Assuntos
Peptídeo 2 Semelhante ao Glucagon/farmacologia , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Animais , Western Blotting , Cardiotônicos/farmacologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica , Receptor do Peptídeo Semelhante ao Glucagon 1 , Receptor do Peptídeo Semelhante ao Glucagon 2 , Coração/efeitos dos fármacos , Técnicas In Vitro , Sistema de Sinalização das MAP Quinases , Masculino , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosforilação , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
10.
Nutr Metab Cardiovasc Dis ; 21(5): 362-71, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20096547

RESUMO

BACKGROUND AND AIMS: Moderate red wine consumption associates with lower incidence of cardiovascular diseases. Attention to the source of this cardioprotection was focused on flavonoids, the non-alcoholic component of the red wine, whose intake inversely correlates with adverse cardiovascular events. We analysed whether two red wine flavonoids, quercetin and myricetin, affect mammalian basal myocardial and coronary function. METHODS AND RESULTS: Quercetin and myricetin effects were evaluated on isolated and Langendorff perfused rat hearts under both basal conditions and α- and ß-adrenergic stimulation. The intracellular signalling involved in the effects of these flavonoids was analysed on perfused hearts and by western blotting on cardiac and HUVEC extracts. Quercetin induced biphasic inotropic and lusitropic effects, positive at lower concentrations and negative at higher concentrations. Contrarily, Myricetin elicits coronary dilation, without affecting contractility and relaxation. Simultaneous administration of the two flavonoids only induced vasodilation. Quercetin-elicited positive inotropism and lusitropism depend on ß1/ß2-adrenergic receptors and associate with increased intracellular cAMP, while the negative inotropism and lusitropism observed at higher concentrations were α-adrenergic-dependent. NOS inhibition abolished Myricetin-elicited vasodilation, also inducing Akt, ERK1/2 and eNOS phosphorylation in both ventricles and HUVEC. Myricetin-dependent vasodilation increases intracellular cGMP and is abolished by triton X-100. CONCLUSIONS: The cardiomodulation elicited on basal mechanical performance by quercetin and the selective vasodilation induced by myricetin point to these flavonoids as potent cardioactive principles, able to protect the heart in the presence of cardiovascular diseases.


Assuntos
Antioxidantes/farmacologia , Flavonoides/farmacologia , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Quercetina/farmacologia , Transdução de Sinais , Vinho , Análise de Variância , Animais , Técnicas In Vitro , Masculino , Octoxinol , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos
11.
Biochim Biophys Acta ; 1787(7): 849-55, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19298789

RESUMO

Being the largest form of intravascular and tissue storage of nitric oxide (NO) and a signalling molecule itself, the nitrite anion (NO(2)(-)) has emerged as a key player in many biological processes. Since the heart is under an important NO-mediated autocrine-paracrine control, in mammals the cardiac effects of nitrite are under intensive investigation. In contrast, nothing is known in non-mammalian vertebrates. We evaluated nitrite influence on cardiac performance in the perfused beating heart of three different cold-blooded vertebrates, i.e. two teleost fishes, the temperate red-blooded Anguilla anguilla, the Antarctic stenotherm, hemoglobinless Chionodraco hamatus (icefish), and the frog Rana esculenta. We showed that, under basal conditions, in all animals nitrite influences cardiac mechanical performance, inducing negative inotropism in eel and frog, while being a positive inotrope in C. hamatus. In all species, these responses parallel the inotropic effects of authentic NO. We also demonstrated that the nitrite-dependent inotropic effects are i) dependent from NO synthase (NOS) activity in fish; ii) sensitive to NO scavenging in frog; iii) cGMP/PKG-dependent in both eel and frog. Results suggest that nitrite is an integral physiological source of NO and acts as a signalling molecule in lower vertebrate hearts, exerting relevant inotropic actions through different species-specific mechanisms.


Assuntos
Anguilla/metabolismo , Contração Miocárdica/efeitos dos fármacos , Nitritos/farmacologia , Perciformes/metabolismo , Rana esculenta/metabolismo , Animais , Regiões Antárticas , Feminino , Masculino , Miocárdio/metabolismo , Oceanos e Mares
12.
FASEB J ; 22(11): 3992-4004, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18697842

RESUMO

Chromogranin A (CGA), produced by human and rat myocardium, generates several biologically active peptides processed at specific proteolytic cleavage sites. A highly conserved cleavage N-terminal site is the bond 64-65 that reproduces the native rat CGA sequence (rCGA1-64), corresponding to human N-terminal CGA-derived vasostatin-1. rCGA1-64 cardiotropic activity has been explored in rat cardiac preparations. In Langendorff perfused rat heart, rCGA1-64 (from 33 nM) induced negative inotropism and lusitropism as well as coronary dilation, counteracting isoproterenol (Iso) - and endothelin-1 (ET-1) -induced positive inotropic effects and ET-1-dependent coronary constriction. rCGA1-64 also depressed basal and Iso-induced contractility on rat papillary muscles, without affecting calcium transients on isolated ventricular cells. Structure-function analysis using three modified peptides on both rat heart and papillary muscles revealed the disulfide bridge requirement for the cardiotropic action. A decline in Iso intrinsic activity in the presence of the peptides indicates a noncompetitive antagonistic action. Experiments on rat isolated cardiomyocytes and bovine aortic endothelial cells indicate that the negative inotropism observed in rat papillary muscle is probably due to an endothelial phosphatidylinositol 3-kinase-dependent nitric oxide release, rather than to a direct action on cardiomyocytes. Taken together, our data strongly suggest that in the rat heart the homologous rCGA1-64 fragment exerts an autocrine/paracrine modulation of myocardial and coronary performance acting as stabilizer against intense excitatory stimuli.


Assuntos
Cromogranina A/metabolismo , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Contração Miocárdica/fisiologia , Miócitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Músculos Papilares/metabolismo , Vasodilatação/fisiologia , Animais , Aorta/citologia , Aorta/metabolismo , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/fisiologia , Cálcio/metabolismo , Cardiotônicos/farmacologia , Bovinos , Cromogranina A/farmacologia , Células Endoteliais/citologia , Endotelina-1/farmacologia , Humanos , Isoproterenol/farmacologia , Masculino , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/citologia , Músculos Papilares/citologia , Comunicação Parácrina/efeitos dos fármacos , Comunicação Parácrina/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacos
13.
Curr Med Chem ; 15(14): 1444-51, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18537621

RESUMO

Over the last 50 years, increasing evidence has documented the ability of cardiac non-neuronal cells to synthesize and release catecholamines (CAs) and the vasorelaxant natriuretic peptides (NPs), which both regulate cardiovascular homeostasis in health and disease. This knowledge has firmly established the concept of the heart as an endocrine organ. The contents of this frame have been richly expanded by the identification of an increasing number of intracardiac endocrine modulators, including Chromogranin-A (CgA) and its derived peptides. In the rat heart, CgA is co-stored and co-released with Atrial NP (ANP) in non-adrenergic myoendocrine atrial cells as well as in atrial and ventricular Purkinje fibres. In the ventricular myocardium of the human hypertrophic and dilated heart, CgA co-localizes with B-type NP (BNP). CgA is the precursor of biologically active peptides produced by proteolytic cleavage. One of them, the human recombinant 1-76 CgA-derived vasostatin-1 (VS-1), is an inhibitor of cardiac contraction and relaxation, a non-competitive counter-regulator of beta-adrenergic stimulation and a protecting agent in ischemic preconditioning. Therefore, it may function as a cardiocirculatory homeostatic stabilizer, particularly in the presence of intense adrenergic stimuli, e. g. under stress responses. Since in patients with chronic heart failure circulating CgA levels increase up to 10-20 nM, depending on the severity of the disease and are independent prognostic indicators of mortality, knowledge on the physio-pathological significance of locally produced and/or circulating CgA-derived peptides, as attemped in this synopsis, may pave the way for clinically-oriented cardiovascular applications.


Assuntos
Cromogranina A/metabolismo , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Fragmentos de Peptídeos/farmacologia , Animais , Cromogranina A/farmacologia , Citoesqueleto/metabolismo , Coração/fisiologia , Hormônios/metabolismo , Humanos , Contração Miocárdica/efeitos dos fármacos , Peptídeo Natriurético Encefálico/metabolismo , Sistemas Neurossecretores/fisiologia , Fragmentos de Peptídeos/metabolismo , Sistema Nervoso Simpático/fisiologia
14.
Acta Physiol (Oxf) ; 223(1): e13035, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29338122

RESUMO

The gasotransmitters nitric oxide (NO), carbon monoxide (CO), and hydrogen sulphide (H2 S), long considered only toxicant, are produced in vivo during the catabolism of common biological molecules and are crucial for a large variety of physiological processes. Mounting evidence is emerging that in poikilotherm vertebrates, as in mammals, they modulate the basal performance of the heart and the response to stress challenges. In this review, we will focus on teleost fish and amphibians to highlight the evolutionary importance in vertebrates of the cardiac control elicited by NO, CO and H2 S, and the conservation of the intracellular cascades they activate. Although many gaps are still present due to discontinuous information, we will use examples obtained by studies from our and other laboratories to illustrate the complexity of the mechanisms that, by involving gasotransmitters, allow beat-to-beat, short-, medium- and long-term cardiac homoeostasis. By presenting the latest data, we will also provide a framework in which the peculiar morpho-functional arrangement of the teleost and amphibian heart can be considered as a reference tool to decipher cardiac regulatory networks which are difficult to explore using more conventional vertebrates, such as mammals.


Assuntos
Anfíbios/metabolismo , Monóxido de Carbono/metabolismo , Peixes/metabolismo , Gasotransmissores/metabolismo , Sulfeto de Hidrogênio/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais , Anfíbios/anatomia & histologia , Animais , Evolução Molecular , Peixes/anatomia & histologia , Homeostase , Humanos , Óxido Nítrico Sintase/metabolismo , Especificidade da Espécie
15.
Acta Physiol (Oxf) ; 223(4): e13067, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29575758

RESUMO

AIM: Selenoprotein T (SelT or SELENOT) is a novel thioredoxin-like enzyme whose genetic ablation in mice results in early embryonic lethality. SelT exerts an essential cytoprotective action during development and after injury through its redox-active catalytic site. This study aimed to determine the expression and regulation of SelT in the mammalian heart in normal and pathological conditions and to evaluate the cardioprotective effect of a SelT-derived peptide, SelT43-52(PSELT) encompassing the redox motif which is key to its function, against ischaemia/reperfusion(I/R) injury. METHODS: We used the isolated Langendorff rat heart model and different analyses by immunohistochemistry, Western blot and ELISA. RESULTS: We found that SelT expression is very abundant in embryo but is undetectable in adult heart. However, SelT expression was tremendously increased after I/R. PSELT (5 nmol/L) was able to induce pharmacological post-conditioning cardioprotection as evidenced by a significant recovery of contractility (dLVP) and reduction of infarct size (IS), without changes in cardiac contracture (LVEDP). In contrast, a control peptide lacking the redox site did not confer cardioprotection. Immunoblot analysis showed that PSELT-dependent cardioprotection is accompanied by a significant increase in phosphorylated Akt, Erk-1/2 and Gsk3α-ß, and a decrement of p38MAPK. PSELT inhibited the pro-apoptotic factors Bax, caspase 3 and cytochrome c and stimulated the anti-apoptotic factor Bcl-2. Furthermore, PSELT significantly reduced several markers of I/R-induced oxidative and nitrosative stress. CONCLUSION: These results unravel the role of SelT as a cardiac modulator and identify PSELT as an effective pharmacological post-conditioning agent able to protect the heart after ischaemic injury.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Selenoproteínas/farmacologia , Tiorredoxina Dissulfeto Redutase/farmacologia , Animais , Antioxidantes/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Modelos Animais de Doenças , Preparação de Coração Isolado , Masculino , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Nitrosativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Ratos Wistar , Selenoproteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
16.
Curr Med Chem ; 14(5): 585-99, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17346149

RESUMO

The intracellular messenger cyclic GMP (cGMP) represents the key signal in several transduction pathways throughout the animal world. In the heart cGMP signaling contributes to functional interaction of different cell types. Nitric oxide (NO) and natriuretic peptides (NPs), major autocrine-paracrine cardiovascular regulators, increment intracellular cGMP through guanylate cyclases (GCs). NO and NPs interact with two GC types: cytosolic (soluble: sGC) and membrane bound [particulate: pGC (NP receptor types A and B)], respectively. Depending on sub-cellular localization and regulation of the enzymes, cGMP produced by either pGC or sGC exerts different complementary effects. The two pathways are reciprocally regulated. NPs-depending pGC is modulated by NO-cGMP signaling, and the activity of NO is influenced by cellular concentrations of both NO itself and NPs. This heterologous feedback regulates GCs, linking cardiovascular autocrine-paracrine activities of NPs and NO. Importance of these cGMP converging routes goes far beyond their role under normal conditions. They are of relevance especially in disease states when tissue and circulating levels of NPs, and local NO production are altered. An example is the endothelial dysfunction associated with deficient NO production and uncoupled endothelium-myocardium communications. In this case, NPs-pGC-cGMP could supplement the reduced activity of NO-scGC-cGMP pathway. In addition, these systems regulate cell growth and apoptosis, playing a role in myocardial pathological morpho-functional remodeling. Here we will review recent concepts on NO/NPs dependent control of heart function in vertebrates, also focusing on cGMP-activated downstream signaling and its role in health and disease conditions.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , GMP Cíclico/biossíntese , Animais , Fenômenos Fisiológicos Cardiovasculares , Guanilato Ciclase/metabolismo , Humanos , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/fisiologia
17.
Acta Physiol (Oxf) ; 214(2): 158-75, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25809182

RESUMO

Recent cardiovascular research showed that, together with ß1- and ß2-adrenergic receptors (ARs), ß3-ARs contribute to the catecholamine (CA)-dependent control of the heart. ß3-ARs structure, function and ligands were investigated in mammals because of their applicative potential in human cardiovascular diseases. Only recently, the concept of a ß3-AR-dependent cardiac modulation was extended to non-mammalian vertebrates, although information is still scarce and fragmentary. ß3-ARs were structurally described in fish, showing a closer relationship to mammalian ß1-AR than ß2-AR. Functional ß3-ARs are present in the cardiac tissue of teleosts and amphibians. As in mammals, activation of these receptors elicits a negative modulation of the inotropic performance through the involvement of the endothelium endocardium (EE), Gi/0 proteins and the nitric oxide (NO) signalling. This review aims to comparatively analyse data from literature on ß3-ARs in mammals, with those on teleosts and amphibians. The purpose is to highlight aspects of uniformity and diversity of ß3-ARs structure, ligands activity, function and signalling cascades throughout vertebrates. This may provide new perspectives aimed to clarify the biological relevance of ß3-ARs in the context of the nervous and humoral control of the heart and its functional plasticity.


Assuntos
Coração/fisiologia , Óxido Nítrico/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Transdução de Sinais/fisiologia , Vertebrados/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Humanos
18.
J Endocrinol ; 227(3): 167-178, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26400960

RESUMO

Serpinin peptides derive from proteolytic cleavage of Chromogranin-A at C-terminus. Serpinin and the more potent pyroglutaminated-serpinin (pGlu-Serp) are positive cardiac ß-adrenergic-like modulators, acting through ß1-AR/AC/cAMP/PKA pathway. Because in some conditions this pathway and/or other pro-survival pathways, activated by other Chromogranin-A fragments, may cross-talk and may be protective, here we explored whether pGlu-Serp cardioprotects against ischemia/reperfusion injury under normotensive and hypertensive conditions. In the latter condition, cardioprotection is often blunted because of the limitations on pro-survival Reperfusion Injury Salvage Kinases (RISK) pathway activation. The effects of pGlu-Serp were evaluated on infarct size (IS) and cardiac function by using the isolated and Langendorff perfused heart of normotensive (Wistar Kyoto, WKY) and spontaneously hypertensive (SHR) rats exposed to ischemic pre-conditioning (PreC) and post-conditioning (PostC). In both WKY and SHR rat, pGlu-Serp induced mild cardioprotection in both PreC and PostC. pGlu-Serp administered at the reperfusion (Serp-PostC) significantly reduced IS, being more protective in SHR than in WKY. Conversely, left ventricular developed pressure (LVDevP) post-ischemic recovery was greater in WKY than in SHR. pGlu-Serp-PostC reduced contracture in both strains. Co-infusion with specific RISK inhibitors (PI3K/Akt, MitoKATP channels and PKC) blocked the pGlu-Serp-PostC protective effects. To show direct effect on cardiomyocytes, we pre-treated H9c2 cells with pGlu-Serp, which were thus protected against hypoxia/reoxygenation. These results suggest pGlu-Serp as a potential modulatory agent implicated in the protective processes that can limit infarct size and overcome the hypertension-induced failure of PostC.


Assuntos
Cromogranina A/uso terapêutico , Hipertensão/complicações , Precondicionamento Isquêmico Miocárdico/métodos , Isquemia Miocárdica/prevenção & controle , Fragmentos de Peptídeos/uso terapêutico , Animais , Cromogranina A/farmacologia , Inibidores Enzimáticos/farmacologia , Hipertensão/metabolismo , Masculino , Isquemia Miocárdica/complicações , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Transdução de Sinais/efeitos dos fármacos
19.
Peptides ; 14(5): 913-8, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8284267

RESUMO

The distribution pattern of rat [125I]-atrial natriuretic factor (ANF) binding sites in the cardiac regions of the Japanese quail was examined by in vitro quantitative autoradiography. Elevated ANF binding densities (519 +/- 121 fmol/mg protein) were found in the posterior vena cava, while lower binding levels (between 40 and 50 fmol/mg protein) were found in sinus venosus, aortic bulb, and endomural vessels, with the ventricular wall having the lowest value (17.6 +/- 8.8 fmol/mg protein). Scatchard analyses of the ANF binding characteristics (Kd, Bmax) revealed both low (94 +/- 55 fmol/mg protein) and high (1161 +/- 69 fmol/mg protein) Bmax values. Receptors with higher Kd values than those observed in other cardiac regions (Kd between 30 and 60 pM) were found in the vena cava and in the heart ventricle (Kd between 113.2 and 229 pM).


Assuntos
Coturnix/metabolismo , Miocárdio/química , Receptores do Fator Natriurético Atrial/análise , Animais , Autorradiografia , Radioisótopos do Iodo
20.
Acta Physiol (Oxf) ; 205(1): 9-25, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22463608

RESUMO

Phospholamban (PLN) is a small phosphoprotein closely associated with the cardiac sarcoplasmic reticulum (SR). Dephosphorylated PLN tonically inhibits the SR Ca-ATPase (SERCA2a), while phosphorylation at Ser16 by PKA and Thr17 by Ca(2+) /calmodulin-dependent protein kinase (CaMKII) relieves the inhibition, and this increases SR Ca(2+) uptake. For this reason, PLN is one of the major determinants of cardiac contractility and relaxation. In this review, we attempted to highlight the functional significance of PLN in vertebrate cardiac physiology. We will refer to the huge literature on mammals in order to describe the molecular characteristics of this protein, its interaction with SERCA2a and its role in the regulation of the mechanic and the electric performance of the heart under basal conditions, in the presence of chemical and physical stresses, such as ß-adrenergic stimulation, response to stretch, force-frequency relationship and intracellular acidosis. Our aim is to provide the basis to discuss the role of PLN also on the cardiac function of nonmammalian vertebrates, because so far this aspect has been almost neglected. Accordingly, when possible, the literature on PLN will be analysed taking into account the nonuniform cardiac structural and functional characteristics encountered in ectothermic vertebrates, such as the peculiar and variable organization of the SR, the large spectrum of response to stresses and the disaptive absence of crucial proteins (i.e. haemoglobinless and myoglobinless species).


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Coração/fisiologia , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Animais , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
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