National Institute of Cardiovascular Research

Bologna, Italy

National Institute of Cardiovascular Research

Bologna, Italy

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Pasqua T.,University of Calabria | Corti A.,San Raffaele Scientific Institute | Gentile S.,University of Calabria | Pochini L.,University of Calabria | And 8 more authors.
Endocrinology | Year: 2013

Plasma chromogranin-A (CgA) concentrations correlate with severe cardiovascular diseases, whereas CgAderived vasostatin-I and catestatin elicit cardiosuppression via an antiadrenergic/nitric oxide-cGMP mediated mechanism. Whether these phenomena are related is unknown.Wehere investigated whether and to what extent full-length CgA directly influences heart performance and may be subjected to stimuluselicited intracardiac processing. Using normotensive and hypertensive rats,weevaluated the following: 1) direct myocardial and coronary effects of full-length CgA; 2) the signal-transduction pathway involved in its action mechanism; and 3) CgA intracardiac processing after β-adrenergic [isoproterenol (Iso)]- and endothelin-1(ET-1)-dependent stimulation. The study was performed by using a Langendorff perfusion apparatus, Western blotting, affinity chromatography, and ELISA.Wefound that CgA (1-4 nM) dilated coronaries and induced negative inotropism and lusitropism, which disappeared at higher concentrations (10-16 nM). In spontaneously hypertensive rats (SHRs), negative inotropism and lusitropism were more potent than inyoungnormotensive rats.Wefound that perfusion itself, Iso-,andendothelin-1 stimulation induced intracardiac CgA processing in low-molecular-weight fragments in young, Wistar Kyoto, and SHR rats. In young normotensive and adult hypertensive rats, CgA increased endothelial nitric oxide synthase phosphorylation and cGMP levels. Analysis of the perfusate from both Wistar rats and SHRs of untreated and treated (Iso) hearts revealed CgA absence. In conclusion, in normotensive and hypertensive rats, we evidenced the following: 1) full-lengthCgAdirectly affects myocardial and coronary function by AkT/nitric oxide synthase/nitric oxide/cGMP/protein kinase G pathway; and 2) the heart generates intracardiac CgA fragments in response to hemodynamic and excitatory challenges. For the first time at the cardiovascular level, our data provide a conceptual link between systemic and intracardiac actions of full-length CgA and its fragments, expanding the knowledge on the sympathochromaffin/CgA axis under normal and physiopathological conditions.


de Lazzari C.,R.Ø.S.A. | de Lazzari C.,National Institute of Cardiovascular Research
Computer Methods in Biomechanics and Biomedical Engineering | Year: 2012

Mathematical modelling of the cardiovascular system (CVS) can help in understanding the complex interactions between both the ventricles and the septum. By describing the behaviour of the left (right) ventricular free wall, atria and septum using the variable elastance models, it is possible to reproduce their interactions. By relating the mechanical properties of both atria and both ventricles to the electrocardiogram (ECG) signal, it is possible to analyse the effects produced by different ECG delay on haemodynamic parameters. In the cardiovascular field, the incorrect interactions between septum and both ventricular free walls are based on many pathological conditions, i.e. symptomatic heart failure resulting from systolic dysfunction, ischemic dilated cardiomyopathy, and so on. The possible corrections that can be induced on the QRS complex duration in the ECG signal (i.e. cardiac resynchronisation therapy, CRT) can produce benefits improving the clinical status of the patient. The aim of this work was to evaluate, using our numerical simulator of the CVS, the effects induced on coronary blood flow (CBF) and aortic pressure using different ECG times, intra-ventricular and inter-ventricular delays. The results were obtained by reproducing the circulatory baseline and CRT conditions of seven patients described in literature. Haemodynamic simulated results are in accordance with literature data. Also the controversial results on CBF, in presence of CRT, are consistent with those described in the literature. © 2012 Copyright Taylor and Francis Group, LLC.


De Lazzari C.,R.Ø.S.A. | De Lazzari C.,National Institute of Cardiovascular Research | Del Prete E.,Instituto Nazionale per lAssicurazione contro gli Infortuni sul Lavoro INAIL | Genuini I.,National Institute of Cardiovascular Research | And 3 more authors.
Computer Methods and Programs in Biomedicine | Year: 2013

In silico modeling of the cardiovascular system (CVS) can help both in understanding pharmacological or pathophysiological process and in providing information which could not be obtained by means of traditional clinical research methods due to practical or ethical reasons. In this work the numerical CVS was used to study the effect of interaction between mechanical ventilation and biventricular pacemaker by haemodynamic and energetic point of view. Starting from literature data on patients with intra and/or inter-ventricular activation time delay and treated using biventricular pacemaker, we used in silico simulator to analyse the effects induced by mechanical ventilatory assistance (MVA). After reproducing baseline and CRT conditions, the MVA was simulated changing the mean intrathoracic pressure value. Results show that simultaneous application of CRT and MVA yields a reduction of cardiac output, left ventricular end-diastolic and end-systolic volume when positive mean intrathoracic pressure is applied. In the same conditions, when MVA is applied, left ventricular ejection fraction, mean left (right) atrial and pulmonary arterial pressure increase. © 2013 Elsevier Ireland Ltd.


Perrelli M.-G.,University of Turin | Perrelli M.-G.,National Institute of Cardiovascular Research | Tullio F.,University of Turin | Tullio F.,National Institute of Cardiovascular Research | And 13 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2013

Catestatin (CST) limits myocardial ischaemia/reperfusion (I/R) injury with unknown mechanisms. Clearly phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) isoforms, including intra-mitochondrial PKCε, mitochondrial K ATP (mitoKATP) channels and subsequent reactive oxygen species (ROS)-signalling play important roles in postconditioning cardioprotection, preventing mitochondrial permeability transition pore (mPTP) opening. Therefore, we studied the role of these extra- and intra-mitochondrial factors in CST-induced protection. Isolated rat hearts and H9c2 cells underwent I/R and oxidative stress, respectively. In isolated hearts CST (75nM, CST-Post) given in early-reperfusion significantly reduced infarct size, limited post-ischaemic contracture, and improved recovery of developed left ventricular pressure. PI3K inhibitor, LY-294002 (LY), large spectrum PKC inhibitor, Chelerythrine (CHE), specific PKCε inhibitor (εV1-2), mitoK ATP channel blocker, 5-Hydroxydecanoate (5HD) or ROS scavenger, 2-mercaptopropionylglycine (MPG) abolished the infarct-sparing effect of CST. Notably the CST-induced contracture limitation was maintained during co-infusion of 5HD, MPG or εV1-2, but it was lost during co-infusion of LY or CHE. In H9c2 cells challenged with H2O2, mitochondrial depolarization (an index of mPTP opening studied with JC1-probe) was drastically limited by CST (75nM). Our results suggest that the protective signalling pathway activated by CST includes mitoKATP channels, ROS signalling and prevention of mPTP opening, with a central role for upstream PI3K/Akt and PKCs. In fact, all inhibitors completely abolished CST-infarct-sparing effect. Since CST-anti-contracture effect cannot be explained by intra-mitochondrial mechanisms (PKCε activation and mitoKATP channel opening) or ROS signalling, it is proposed that these downstream signals are part of a reverberant loop which re-activates upstream PKCs, which therefore play a pivotal role in CST-induced protection. © 2013 Springer-Verlag Berlin Heidelberg.


Penna C.,University of Turin | Penna C.,National Institute of Cardiovascular Research | Alloatti G.,University of Turin | Alloatti G.,National Institute of Cardiovascular Research | And 17 more authors.
Cellular and Molecular Neurobiology | Year: 2010

The Chromogranin A (CgA)-derived anti-hypertensive peptide catestatin (CST) antagonizes catecholamine secretion, and is a negative myocardial inotrope acting via a nitric oxide-dependent mechanism. It is not known whether CST contributes to ischemia/reperfusion injury or is a component of a cardioprotective response to limit injury. Here, we tested whether CST by virtue of its negative inotropic activity improves post-ischemic cardiac function and cardiomyocyte survival. Three groups of isolated perfused hearts from adult Wistar rats underwent 30-min ischemia and 120-min reperfusion (I/R, Group 1), or were post-conditioned by brief ischemic episodes (PostC, 5-cycles of 10-s I/R at the beginning of 120-min reperfusion, Group 2), or with exogenous CST (75 nM for 20 min, CST-Post, Group-3) at the onset of reperfusion. Perfusion pressure and left ventricular pressure (LVP) were monitored. Infarct size was evaluated with nitroblue-tetrazolium staining. The CST (5 nM) effects were also tested in simulated ischemia/reperfusion experiments on cardiomyocytes isolated from young-adult rats, evaluating cell survival with propidium iodide labeling. Infarct size was 61 ± 6% of risk area in hearts subjected to I/R only. PostC reduced infarct size to 34 ± 5%. Infarct size in CST-Post was 36 ± 3% of risk area (P < 0.05 respect to I/R). CST-Post reduced post-ischemic rise of diastolic LVP, an index of contracture, and significantly improved post-ischemic recovery of developed LVP. In isolated cardiomyocytes, CST increased the cell viability rate by about 65% after simulated ischemia/reperfusion. These results suggest a novel cardioprotective role for CST, which appears mainly due to a direct reduction of post-ischemic myocardial damages and dysfunction, rather than to an involvement of adrenergic terminals and/or endothelium. © 2010 The Author(s).


Quintieri A.M.,University of Calabria | Filice E.,University of Calabria | Amelio D.,University of Calabria | Pasqua T.,University of Calabria | And 11 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2016

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. © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.


Penna C.,University of Turin | Pasqua T.,University of Calabria | Amelio D.,University of Calabria | Perrelli M.-G.,University of Turin | And 11 more authors.
PLoS ONE | Year: 2014

Background: In the presence of comorbidities the effectiveness of many cardioprotective strategies is blunted. The goal of this study was to assess in a hypertensive rat model if the early reperfusion with anti-hypertensive and pro-angiogenic Chromogranin A-derived peptide, Catestatin (CST:hCgA 352-372; CST-Post), protects the heart via Reperfusion-Injury- Salvage-Kinases (RISK)-pathway activation, limiting infarct-size and apoptosis, and promoting angiogenetic factors (e.g., hypoxia inducible factor, HIF-1α, and endothelial nitric oxide synthase, eNOS, expression). Methods and Results: The effects of CST-Post on infarct-size, apoptosis and pro-angiogenetic factors were studied in isolated hearts of spontaneously hypertensive rats (SHR), which underwent the following protocols: (a) 30-min ischemia and 120-min reperfusion (I/R); (b) 30-min ischemia and 20-min reperfusion (I/R-short), both with and without CST-Post (75 nM for 20-min at the beginning of reperfusion). In unprotected Wistar-Kyoto hearts, used as normal counterpart, infarct-size resulted smaller than in SHR. CST-Post reduced significantly infarct-size and improved post-ischemic cardiac function in both strains. After 20-min reperfusion, CST-Post induced S-nitrosylation of calcium channels and phosphorylation of RISKpathway in WKY and SHR hearts. Yet specific inhibitors of the RISK pathway blocked the CST-Post protective effects against infarct in the 120-min reperfusion groups. Moreover, apoptosis (evaluated by TUNEL, ARC and cleaved caspase) was reduced by CST-Post. Importantly, CST-Post increased expression of pro-angiogenetic factors (i.e., HIF-1α and eNOS expression) after two-hour reperfusion. Conclusions: CST-Post limits reperfusion damages and reverses the hypertension-induced increase of I/R susceptibility. Moreover, CST-Post triggers antiapoptotic and pro-angiogenetic factors suggesting that CST-Post can be used as an anti-maladaptive remodeling treatment. © 2014 Penna et al.


Angelone T.,University of Calabria | Angelone T.,National Institute of Cardiovascular Research | Quintieri A.M.,University of Calabria | Pasqua T.,University of Calabria | And 8 more authors.
Nitric Oxide - Biology and Chemistry | Year: 2015

Abstract 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. © 2015 Elsevier Inc.


Pasqua T.,University of Calabria | Filice E.,University of Calabria | Mazza R.,University of Calabria | Quintieri A.M.,University of Calabria | And 8 more authors.
Journal of Cellular and Molecular Medicine | Year: 2015

Heat shock proteins (HSPs), highly conserved in all organisms, act as molecular chaperones activated by several stresses. The HSP70 class of stress-induced proteins is the most studied subtype in cardiovascular and inflammatory disease. Because of the high similarity between plant and mammalian HSP70, the aim of this work was to evaluate whether recombinant HSP70 of plant origin (r-AtHSP70) was able to protect rat cardiac and hepatic function under ischemic and sepsis conditions. We demonstrated for the first time that, in ex vivo isolated and perfused rat heart, exogenous r-AtHSP70 exerted direct negative inotropic and lusitropic effects via Akt/endothelial nitric oxide synthase pathway, induced post-conditioning cardioprotection via Reperfusion Injury Salvage Kinase and Survivor Activating Factor Enhancement pathways, and did not cause hepatic damage. In vivo administration of r-AtHSP70 protected both heart and liver against lipopolysaccharide-dependent sepsis, as revealed by the reduced plasma levels of interleukin-1β, tumour necrosis factor alpha, aspartate aminotransferase and alanine aminotransferase. These results suggest exogenous r-AtHSP70 as a molecular modulator able to protect myocardial function and to prevent cardiac and liver dysfunctions during inflammatory conditions. © 2015 The Authors.


Imbrogno S.,University of Calabria | Gattuso A.,University of Calabria | Mazza R.,University of Calabria | Angelone T.,University of Calabria | And 3 more authors.
Acta Physiologica | Year: 2015

Recent cardiovascular research showed that, together with β1- and β2-adrenergic receptors (ARs), β3-ARs contribute to the catecholamine (CA)-dependent control of the heart. β3-ARs structure, function and ligands were investigated in mammals because of their applicative potential in human cardiovascular diseases. Only recently, the concept of a β3-AR-dependent cardiac modulation was extended to non-mammalian vertebrates, although information is still scarce and fragmentary. β3-ARs were structurally described in fish, showing a closer relationship to mammalian β1-AR than β2-AR. Functional β3-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 β3-ARs in mammals, with those on teleosts and amphibians. The purpose is to highlight aspects of uniformity and diversity of β3-ARs structure, ligands activity, function and signalling cascades throughout vertebrates. This may provide new perspectives aimed to clarify the biological relevance of β3-ARs in the context of the nervous and humoral control of the heart and its functional plasticity. © 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

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