RESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells following binding with the cell surface ACE2 receptors, thereby leading to coronavirus disease 2019 (COVID-19). SARS-CoV-2 causes viral pneumonia with additional extrapulmonary manifestations and major complications, including acute myocardial injury, arrhythmia, and shock mainly in elderly patients. Furthermore, patients with existing cardiovascular comorbidities, such as hypertension and coronary heart disease, have a worse clinical outcome following contraction of the viral illness. A striking feature of COVID-19 pandemics is the high incidence of fatalities in advanced aged patients: this might be due to the prevalence of frailty and cardiovascular disease increase with age due to endothelial dysfunction and loss of endogenous cardioprotective mechanisms. Although experimental evidence on this topic is still at its infancy, the aim of this position paper is to hypothesize and discuss more suggestive cellular and molecular mechanisms whereby SARS-CoV-2 may lead to detrimental consequences to the cardiovascular system. We will focus on aging, cytokine storm, NLRP3/inflammasome, hypoxemia, and air pollution, which is an emerging cardiovascular risk factor associated with rapid urbanization and globalization. We will finally discuss the impact of clinically available CV drugs on the clinical course of COVID-19 patients. Understanding the role played by SARS-CoV2 on the CV system is indeed mandatory to get further insights into COVID-19 pathogenesis and to design a therapeutic strategy of cardio-protection for frail patients.
Asunto(s)
Betacoronavirus , Enfermedades Cardiovasculares/virología , Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Factores de Edad , Anciano , COVID-19 , Enfermedades Cardiovasculares/epidemiología , Infecciones por Coronavirus/epidemiología , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/epidemiología , Factores de Riesgo , SARS-CoV-2RESUMEN
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.
Asunto(s)
Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Selenoproteínas/farmacología , Reductasa de Tiorredoxina-Disulfuro/farmacología , Animales , Antioxidantes/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Modelos Animales de Enfermedad , Preparación de Corazón Aislado , Masculino , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Estrés Nitrosativo/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Ratas Wistar , Selenoproteínas/metabolismo , Transducción de Señal/efectos de los fármacos , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
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.
Asunto(s)
Anfibios/metabolismo , Cromogranina A/genética , Corazón/efectos de los fármacos , Miocardio/metabolismo , Simpatomiméticos/metabolismo , Animales , Fragmentos de Péptidos/metabolismo , Transducción de SeñalRESUMEN
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.
Asunto(s)
Suplementos Dietéticos , Síndrome Metabólico/prevención & control , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Obesidad Abdominal/prevención & control , Aceite de Oliva/administración & dosificación , Grasa Abdominal/metabolismo , Grasa Abdominal/fisiopatología , Adiposidad , Alimentación Animal , Animales , Apoptosis , Biomarcadores/sangre , Glucemia/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Dislipidemias/sangre , Dislipidemias/etiología , Dislipidemias/prevención & control , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Intolerancia a la Glucosa/sangre , Intolerancia a la Glucosa/etiología , Intolerancia a la Glucosa/prevención & control , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/prevención & control , Preparación de Corazón Aislado , Lípidos/sangre , Hígado/metabolismo , Hígado/patología , Síndrome Metabólico/sangre , Síndrome Metabólico/etiología , Síndrome Metabólico/fisiopatología , Infarto del Miocardio/sangre , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/sangre , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Obesidad Abdominal/sangre , Obesidad Abdominal/etiología , Obesidad Abdominal/fisiopatología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas Sprague-Dawley , Receptor IGF Tipo 1/metabolismo , Transducción de Señal , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
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.
Asunto(s)
Cromogranina A/uso terapéutico , Hipertensión/complicaciones , Precondicionamiento Isquémico Miocárdico/métodos , Isquemia Miocárdica/prevención & control , Fragmentos de Péptidos/uso terapéutico , Animales , Cromogranina A/farmacología , Inhibidores Enzimáticos/farmacología , Hipertensión/metabolismo , Masculino , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Fragmentos de Péptidos/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal/efectos de los fármacosRESUMEN
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.
RESUMEN
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.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/farmacología , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Proteínas de Unión al ADN/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Corazón/fisiología , Proteínas del Tejido Nervioso/farmacología , Animales , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Carpa Dorada , Corazón/efectos de los fármacos , NucleobindinasRESUMEN
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.
Asunto(s)
Corazón/fisiología , Óxido Nítrico/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Transducción de Señal/fisiología , Vertebrados/metabolismo , Agonistas Adrenérgicos beta/farmacología , Animales , HumanosRESUMEN
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.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al ADN/metabolismo , Miocardio/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Daño por Reperfusión/metabolismo , Secuencia de Aminoácidos , Animales , Proteínas de Unión al Calcio/química , Proteínas de Unión al Calcio/genética , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Canales KATP/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Óxido Nítrico/metabolismo , Nucleobindinas , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores del Factor Natriurético Atrial/metabolismo , Daño por Reperfusión/patología , Transducción de SeñalRESUMEN
Chromogranin A (CgA), a major component of the chromaffin granules, is co-stored and co-released with catecholamines. It is also expressed in extra-adrenal sites, including the heart. In the rat, CgA localizes in atrial myoendocrine cells, associated with Atrial Natriuretic Peptide (ANP), and in the conduction system. In the human heart it is present in the ventricular myocardium, co-localized with B-type NP (BNP). CgA is the precursor of several biologically active peptides generated by proteolytic processing also in the heart. Two of them, vasostatin-1 (VS-1) and catestatin (Cst), inhibit cardiac contraction and relaxation, counter-regulate beta-adrenergic and endothelinergic stimulation, and protect the heart against ischemia/reperfusion damages. Recently, clinical studies have suggested CgA to be involved also in cardiovascular pathologies. High plasma CgA levels were found in hypertension, chronic and acute heart failure, myocardial infarction, decompensated and hypertrophic heart, and acute coronary syndromes. These alterations correlate with those of conventional cardiovascular biomarkers, such as NP and endothelin-1 (ET-1), and have prognostic relevance, being indicative of both severity of the disease and mortality. Accordingly, the current knowledge indicates CgA as a multifaceted peptide in cardiovascular homeostasis. Whether the influence elicited by the protein on both normal and failing heart is beneficial and/or detrimental, as well as its implication in the cardiac neuroendocrine scenario is under intense investigation. This review will focus on: i) the involvement of CgA and its derived peptides in the mechanisms which sustain cardiac function and compensation, ii) CgA clinical relevance, and iii) its putative value as a clinical biomarker.
Asunto(s)
Cromogranina A/metabolismo , Animales , Biomarcadores/metabolismo , Gránulos Cromafines/metabolismo , Cromogranina A/sangre , Cardiopatías/metabolismo , Cardiopatías/patología , Humanos , Hipertensión/metabolismo , Hipertensión/patología , Miocardio/metabolismo , Péptidos Natriuréticos/metabolismo , Serpinas/metabolismoRESUMEN
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.
Asunto(s)
Péptido 2 Similar al Glucagón/farmacología , Receptores de Glucagón/genética , Receptores de Glucagón/metabolismo , Animales , Western Blotting , Cardiotónicos/farmacología , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/genética , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica , Receptor del Péptido 1 Similar al Glucagón , Receptor del Péptido 2 Similar al Glucagón , Corazón/efectos de los fármacos , Técnicas In Vitro , Sistema de Señalización de MAP Quinasas , Masculino , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fragmentos de Péptidos/farmacología , Fosforilación , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de SeñalRESUMEN
The richly structured neuroendocrine control of the heart in health and disease requires, in addition to the autonomic nervous outflow, the essential contribute of various and often interacting humoral peptides (e.g. natriuretic peptides, Chromogranin-A-derived fragments, etc). In many cases, these molecules also influence the activity of other organ systems, including the gastrointestinal apparatus, in which they control mucosal function as well as motility and secretion. Interestingly, by acting centrally, some of these peptides also regulate satiety and appetite, thus forming an interesting link between cardiac and gastrointestinal function, and the feeding pattern. Prolonged inhibition and/or activation of these peptide pathways frequently results in severe and long-lasting dysfunctions, including cardiovascular diseases associated to alimentary disorders (e.g. obesity). Notably, their multifarious actions and mutual interactions make them excellent candidates for long-term resetting of both cardiac, gastrointestinal and nutrition homeostasis. Here we will provide only few examples taken from the quickly evolving scenario, with the purpose to provide indications concerning the complex circuits generated by multilevel signalling peptides, which contributes to orchestrate the association between cardiovascular, gastrointestinal and alimentary functions. This will highlight not only the complexity of the cardiovascular and GI regulatory networks, but also aspects of integration between feeding stimulating peptides and the other neuroendocrine systems affecting the heart and the GI tract.
Asunto(s)
Fenómenos Fisiológicos Cardiovasculares , Sistema Endocrino/fisiología , Tracto Gastrointestinal/fisiología , Hipotálamo/fisiología , Sistemas Neurosecretores/fisiología , Animales , Sistema Cardiovascular/metabolismo , Sistema Endocrino/metabolismo , Tracto Gastrointestinal/metabolismo , Ghrelina/metabolismo , Humanos , Hipotálamo/metabolismo , Péptidos Natriuréticos , Neuropéptido Y/metabolismo , Sistemas Neurosecretores/metabolismoRESUMEN
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.
Asunto(s)
Antioxidantes/farmacología , Flavonoides/farmacología , Corazón/efectos de los fármacos , Miocardio/metabolismo , Quercetina/farmacología , Transducción de Señal , Vino , Análisis de Varianza , Animales , Técnicas In Vitro , Masculino , Octoxinol , Ratas , Ratas Wistar , Vasodilatación/efectos de los fármacosRESUMEN
Recently, the circulating anion nitrite (NO2-), the largest physiological reservoir of nitric oxide (NO) in the body, has revealed itself as a signalling molecule mediating numerous biological responses. Since it was estimated that as much as 70% of plasma nitrite originates from nitric oxide synthases (NOSs), mainly in the endothelium by endothelial NOS, nitrite is considered an index of NOSs activity. Exogenous sources, principally environmental pollutants and intake of vegetables, also contribute to this NO reserve. In mammalian blood, nitrite, present at nanomolar concentrations, can be reduced to bioactive NO along a physiological oxygen and pH gradient either non-enzymatically (acidic disproportionation) or by a number of enzymes including xanthine oxidoreductase, NOS, mitochondrial cytochromes and deoxygenated haemoglobin and myoglobin. The various NO-dependent nitrite-induced biological responses include hypoxic vasodilation, inhibition of mitochondrial respiration, cytoprotection following ischemia/reperfusion, and regulation of protein and gene expression. Since NO is a major paracrine-autocrine cardiovascular modulator and nitrite acts mainly as an endocrine store of NO, it is not surprising that NO2 - exerts important cardiovascular actions both under normal and physio-pathological conditions. In the interdisciplinary framework of the NO cycle concept, this review illustrates the actions exerted by nitrite on the cardiovascular system. Since the majority of the NO2 - -oriented studies focused on the systemic and regional control of blood flow both under physiological and ischemia/reperfusion conditions, we will firstly consider this issue. Secondly, the nitrite- induced effects on myocardial contractile and relaxation processes will be discussed, emphasizing the biomedical interest of nitrite as a new therapeutic agent. The importance of cardiac myoglobin as nitrite-reductase able to exert cardioprotection through a novel function, in addition to its role as classical respiratory protein, will be highlighted. Finally, using recent data from others and our labs, we will emphasize the importance of fish and amphibian heart models with diverse morphologies and blood supply for providing remarkable insights on "ancestral" functions of the nitrite-NO system in vertebrates, which, in turn, may help to expand its actual significance in human physiology.
Asunto(s)
Cardiotónicos/metabolismo , Cardiotónicos/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Sistema Cardiovascular/metabolismo , Nitritos/metabolismo , Nitritos/uso terapéutico , Animales , Sistema Cardiovascular/patología , Humanos , Óxido Nítrico/metabolismo , Nitrito Reductasas/metabolismoRESUMEN
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.
Asunto(s)
Anguilla/metabolismo , Contracción Miocárdica/efectos de los fármacos , Nitritos/farmacología , Perciformes/metabolismo , Rana esculenta/metabolismo , Animales , Regiones Antárticas , Femenino , Masculino , Miocardio/metabolismo , Océanos y MaresRESUMEN
In the present study, we evaluated the transduction pathways involved in the cardiac effects elicited by 17beta-estradiol (E2) on the isolated, Langendorff perfused male Wistar rat heart. E2 and selective agonists for ERalpha and ERbeta induced a dose-dependent reduction of contractility which was blocked by the ER inhibitor ICI 182,780. Moreover, the potential involvement of the novel membrane estrogen receptor GPR30 in mediating estrogen activity was determined using the selective GPR30 ligand G-1. Notably, specific inhibitors of ERK, PI3K, PKA, and eNOS transduction pathways abolished the cardiac responses to E(2). Taken together, our data suggest that ERalpha and ERbeta along with several signaling cascades are involved in the action of E(2) on the male rat heart. Our results also point to a potential role of GPR30, however further evaluation is required in order to fully understand the contribution of the different estrogen receptors in mediating estrogen activity on cardiac performance.
Asunto(s)
Estradiol/farmacología , Corazón/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/antagonistas & inhibidores , Expresión Génica , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Masculino , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Presión Ventricular/efectos de los fármacosRESUMEN
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.
Asunto(s)
Cromogranina A/metabolismo , Vasos Coronarios/metabolismo , Células Endoteliales/metabolismo , Contracción Miocárdica/fisiología , Miocitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Músculos Papilares/metabolismo , Vasodilatación/fisiología , Animales , Aorta/citología , Aorta/metabolismo , Comunicación Autocrina/efectos de los fármacos , Comunicación Autocrina/fisiología , Calcio/metabolismo , Cardiotónicos/farmacología , Bovinos , Cromogranina A/farmacología , Células Endoteliales/citología , Endotelina-1/farmacología , Humanos , Isoproterenol/farmacología , Masculino , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/citología , Músculos Papilares/citología , Comunicación Paracrina/efectos de los fármacos , Comunicación Paracrina/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Wistar , Relación Estructura-Actividad , Vasodilatación/efectos de los fármacosRESUMEN
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.