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 KATP 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.
Abstract Objective Brain processing at varying levels of functional complexity has been documented in vegetative state. In this study, data mining procedures are applied to identify significant ...changes in heart rate variability (an emerging objective descriptor of autonomic correlates of brain activation) in response to complex auditory stimuli with emotional value (music). Methods The heart rate of subjects in vegetative state from brain damage ( n = 6) or spontaneous hemorrhage ( n = 3) and 16 healthy controls was recorded while they passively listened to four pre-selected music samples by different authors (mean recording time: 3 m and 36 s ± 24 s). The parametric and non-parametric frequency spectra were computed on the heart rate, spectra were compared within/across subjects and music authors, and the spectra descriptors were entered into a 1-R rules data mining procedure (WEKA software Leave One Out and Ten Fold Cross validation). The procedure independently classified the heart rate spectral patterns of both patients and controls and the emotions reported by healthy subjects as “ positive ” or “ negative ”. Results In both healthy controls and vegetative state subjects, the power spectra while passively listening to music differed from baseline when compared irrespective of the music authorship and from each other when compared across music samples. Data mining sorted the nu_LF (normalized parameter unit of the spectrum low frequency range) as the significant descriptor of heart rate variability in the conditions of the study. The nu_LF classification of the healthy controls’ HRV changes in response to music replicated that based on subjective reports with 75–93.7% accuracy. Conclusions Although preliminary, these findings suggest that autonomic changes with possible emotional value can be induced by complex stimuli also in vegetative state, with implications on the residual responsiveness of these subjects. Significance Heart rate variability descriptors and data mining methods appear applicable to investigate brain function in the absence of consciousness.
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.
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.
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.--Cerra, M. C., Gallo, M. P., Angelone, T., Quintieri, A. M., Pulerà, E., Filice, E., Guérold, B., Shooshtarizadeh, P., Levi, R., Ramella, R., Brero, A., Boero, O., Metz-Boutigue, M. H., Tota, B., Alloatti, G. The homologous rat chromogranin A1-64 (rCGA1-64) modulates myocardial and coronary function in rat heart to counteract adrenergic stimulation indirectly via endothelium-derived nitric oxide.
Background and purpose: Residual brain function has been documented in vegetative state patients, yet early prognosis remains difficult. The purpose of this study was to identify by artificial ...intelligence procedures (classification and regression trees, data-mining) the significant neurological signs correlated to and predictive of outcome.
Methods: Three hundred and thirty-three patients in vegetative state of traumatic or non-traumatic aetiology referred to the S.Anna Institute were retrospectively studied. Twenty-two neurological signs were assessed according to criteria included in the UNI ENI ISO 9001 : 2000 quality standards at admission (Time0) and after 50, 100 or 180 days and entered into a CART (classification and regression tree) data-mining procedure with a decisional tree j48 (Weka software and 10-fold cross-validation). Outcome was conventionally rated by the Glasgow outcome scale.
Results and conclusions: Re-appearance with proper timing of spontaneous motility, eye tracking and oculo-cephalic reflex and disappearance of oral automatisms proved highly correlated to outcome and allowed early and reliable prognosis. These findings are consistent with the brain functional organization thought to sustain consciousness and warrant systematic investigation. Classification and regression trees and data-mining procedures proved applicable in neurology to sort out significant clinical signs also in clinical conditions characterized by paucity of signs such as the vegetative state. Extended application in clinical medicine is conceivable based on the approach peculiarities.
The antihypertensive flavonol quercetin (Q1) is endowed with a cardioprotective effect against myocardial ischemic damage. Q1 inhibits angiotensin converting enzyme activity, improves vascular ...relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium.
In the aim to overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties.
Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with β-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively.
Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10−8M÷10−6M doses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10−10M and 10−8÷10−6M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both β1/β2-adrenergic receptors.
Taking into consideration all the obtained results, the replacement of OH with ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension.
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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.
•CST positively influences the Frank–Starling response in both normotensive and hypertensive hearts.•This modulation involves the VE, the PI3K/NO/cGMP pathway and protein S-Nitrosylation.•CTS acts as an endogenous nitric oxide stimulator.
The purpose of the study was to identify significant changes in heart rate variability (an emerging descriptor of emotional conditions; HRV) concomitant to complex auditory stimuli with emotional ...value (music). In healthy controls, traumatic brain injured (TBI) patients, and subjects in the vegetative state (VS) the heart beat was continuously recorded while the subjects were passively listening to each of four music samples of different authorship. The heart rate (parametric and nonparametric) frequency spectra were computed and the spectra descriptors were processed by data-mining procedures. Data-mining sorted the nu_lf (normalized parameter unit of the spectrum low frequency range) as the significant descriptor by which the healthy controls, TBI patients, and VS subjects' HRV responses to music could be clustered in classes matching those defined by the controls and TBI patients' subjective reports. These findings promote the potential for HRV to reflect complex emotional stimuli and suggest that residual emotional reactions continue to occur in VS. HRV descriptors and data-mining appear applicable in brain function research in the absence of consciousness.
Abstract 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.
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