Recombinant N-terminal fragments of chromogranin-A modulate cardiac function of the Langendorff-perfused rat heart. Basic Research in Cardiology

Department of Pharmaco-Biology, University of Calabria, 87030, Arcavacata di Rende (CS), Italy.
Archiv für Kreislaufforschung (Impact Factor: 5.41). 02/2006; 101(1):43-52. DOI: 10.1007/s00395-005-0547-2
Source: PubMed


In this study we tested the hypothesis that vasostatins could act as myocardial modulators in the mammalian heart. Using the Langendorff-perfused rat heart, the cardiac effects of the two recombinant human CGA N-terminal fragments STA-CGA1-78 and STA-CGA1-115, containing the vasostatin-1 (CGA 1-76) and vasostatin-2 (CGA 1-113) sequences, respectively, were evaluated at concentrations of 11 / 165 nM. Cardiac performance was evaluated by analyzing left ventricular pressure (LVP) and the rate pressure product (RPP: HR x LVP), used as indexes of contractile activity and cardiac work, respectively. Under basal conditions, STA-CGA1-78 at all concentrations tested elicited a dose-dependent negative inotropism (LVP variations ranging from -9.6% +/- 2 to -23% +/- 2.9) without affecting coronary pressure (CP). In contrast, STA-CGA1-115 increased CP at 110 and 165 nM without affecting inotropism. Both STA-CGA1-78 and STA-CGA1-115 counteracted the cardio-stimulatory effects of isoproterenol (ISO). The ISO-dependent positive chronotropism was unaffected by STA-CGA1-78, while being reduced by STA-CGA1-115. Both peptides abolished the ISO-induced positive inotropism without modifying either the beta-adrenergic-dependent coronary dilation or the ouabain-induced positive inotropism. The analysis of the percentage of variations of RPP in terms of EC50 values of ISO alone (-8.5 +/- 0.3; r2 = 0.88) and in presence of STA-CGA1-78 (11, or 33, or 65 nM: -7.7 +/- 0.15, r2 = 0.97; -7.7 +/- 0.15, r2 = 0.97; -7.8 +/- 0.78, r2 = 0.55, respectively) revealed a non-competitive type of antagonism of STA-CGA1-78. Taken together, these data suggest vasostatins as novel cardioregulatory peptides in mammals.

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    • "The analysis of the percentage of variations of LVP, which provides the EC50 values in the presence of either increasing concentrations of ISO alone or of ISO plus rCGA 1-64 (11, 33, and 65 nM), showed that rCGA1-64 elicits its anti-β-adrenergic action through a functional non-competitive antagonism, confirming the results obtained with the human VS-1 (Cerra et al., 2006). "
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    ABSTRACT: Together with Chromogranin B and Secretogranins, Chromogranin A (CGA) is stored in secretory (chromaffin) granules of the diffuse neuroendocrine system and released with noradrenalin and adrenalin. Co-stored within the granule together with neuropeptideY, cardiac natriuretic peptide hormones, several prohormones and their proteolytic enzymes, CGA is a multifunctional protein and a major marker of the sympatho-adrenal neuroendocrine activity. Due to its partial processing to several biologically active peptides, CGA appears an important pro-hormone implicated in relevant modulatory actions on endocrine, cardiovascular, metabolic, and immune systems through both direct and indirect sympatho-adrenergic interactions. As a part of this scenario, we here illustrate the emerging role exerted by the full-length CGA and its three derived fragments, i.e., Vasostatin 1, catestatin and serpinin, in the control of circulatory homeostasis with particular emphasis on their cardio-vascular actions under both physiological and physio-pathological conditions. The Vasostatin 1- and catestatin-induced cardiodepressive influences are achieved through anti-beta-adrenergic-NO-cGMP signaling, while serpinin acts like beta1-adrenergic agonist through AD-cAMP-independent NO signaling. On the whole, these actions contribute to widen our knowledge regarding the sympatho-chromaffin control of the cardiovascular system and its highly integrated "whip-brake" networks.
    Frontiers in Chemistry 08/2014; 2:64. DOI:10.3389/fchem.2014.00064
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    • "Vasostatin-1 (VS-1) is a recently identified regulatory peptides derived from the N-terminal domain of chromogranin A (CGA), which is not only secreted by granules of several endocrine and neuronal cells (Tota et al., 2007), but is produced by human myocardium (Cerra et al., 2008). There is strong evidence that VS-1, which is highly expressed in cardiovascular stress region, can cause vasodilation, enhance innate immunity, promote cell adhesion and inhibit the production of inflammatory cytokines to keep the balance of cardiovascular homeostasis (Brekke et al., 2002; Blois et al., 2006; Cerra et al., 2006; Helle, 2010). Cappello et al. (2007) and Pagliaro et al. (2007) report that, VS-1 with the concentration of more than 33 nmol/L can produce an ischemic preconditioning-like anti-myocardial ischemia reperfusion injury (MIRI) effects on myocardial cells. "
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    ABSTRACT: Vasostatin-1 (VS-1) has been proved to play important roles in myocardial ischemia/reperfusion injury. This study further explored the protective effects of VS-1 on cardiomyocytes using cardiomyocytes - endothelial cells Transwell Co-culture System. Cardiomyocytes and rat aortic endothelial cells (RAECs) were respectively prepared from ventricles and thoraco-abdominal aorta of Sprague-Dawley rats. The experiment was divided into cardiomyocytes alone culture group (C) and cardiomyocytes-RAECs co-culture group (T), each with three subgroups: C-Ad-Null, C-Ad-VS-1, C-Hb (Ad-VS-1 + NO scavenger Hb), or T-Ad-Null, T-Ad-VS-1 transfection, T-Hb. After 48-hour incubation, all groups were treated with hypoxia for 60 minutes and then reoxygenated for 120 minutes. We also investigated endothelial cells -mediated cardiomyocytes protection. RAECs were treated with hypoxia for 30 minutes and reoxygenated with normal cardiomyocytes for 120 minutes. The cardiomyocytes apoptosis rate, aspartate aminotransferase (AST) and creatine kinase isozyme MB (CK-MB) were recorded. As expected, the cardiomyocytes apoptosis, AST and CK-MB were significantly increased in the T-Ad-Null group than those in the C-Ad-Null group. VS transfection significantly reduced the above levels. However, the apoptosis rate, AST and CK-MB levels were re-increased after Hb treatment, which returned to the similar level of C-Ad-null group in the C-Hb group, but still significantly lower in the T-Hb group compared with the T-Ad-null group. Interestingly, RAECs injury caused cardiomyocytes injury and VS-1 transfection to the RAECs decreased the apoptosis rate of cardiomyocytes and the levels of AST and CK-MB. Our findings suggest that VS-1 exerts protective effects on the cardiomyocytes directly or indirectly by cardiomyocytes-endothelial cells interaction.
    Cell Biology International 01/2014; 38(1). DOI:10.1002/cbin.10166 · 1.93 Impact Factor
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    • "Vasostatin I fragment (CgA 17–39 ) is found as a circulating peptide in mammals (Stridsberg et al., 2000) and can produce peripheral cardiovascular effects, including suppression of blood vessel contraction (Aardal and Helle, 1992; Aardal et al., 1993; Brekke et al., 2002). Recently both vasostatin I and catestatin were reported to induce a negative inotropic effect on the isolated rat heart under basal conditions and after β-adrenergic stimulation (Cerra et al., 2006; Angelone et al., 2008). While CgA peptide products clearly have peripheral cardiovascular effects, the function of these peptides within the central nervous system is less clear. "
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    ABSTRACT: Vasostatin I (CgA(1-76)) is a naturally occurring biologically active peptide derived from chromogranin A (CgA), and is so named for its inhibitory effects on vascular tension. CgA mRNA is expressed abundantly in sympathoexcitatory catecholaminergic neurons of the rostral ventrolateral medulla (RVLM). CgA microinjection into the RVLM decreases blood pressure (BP), heart rate (HR) and sympathetic nerve activity (SNA). Proteolytic fragments of CgA are thought to be responsible for the cardiovascular effects observed. We hypothesised that vasostatin I is one of the fragments responsible for the central effects of CgA. We examined the role of a vasostatin I fragment, CgA(17-76) (VS-I((CgA17-76))), containing the portion important for biological effects. The effects of VS-I((CgA17-76)) delivered by intrathecal injection, or microinjection into the RVLM, on cardio-respiratory function in urethane anaesthetised, vagotomised, mechanically ventilated Sprague-Dawley rats (n=21) were evaluated. The effects of intrathecal VS-I((CgA17-76)) on the somato-sympathetic, baroreceptor and peripheral chemoreceptor reflexes were also examined. At the concentrations used (10, 100 or 200 μM, intrathecal; or 5 μM, RVLM microinjection) VS-I((CgA17-76)) produced no change in mean arterial pressure, HR, splanchnic SNA, phrenic nerve amplitude or phrenic nerve frequency. All reflexes examined were unchanged following intrathecal VS-I((CgA17-76)). In the periphery, VS-I((CgA17-76)) potentiated the contractile effects of noradrenaline on rat mesenteric arteries (n=6), with a significant left-shift in the dose response curve to noradrenaline (3.7×10(-7) vs 7.7×10(-7)). Our results indicate that VS-I((CgA17-76)) is active in the periphery but not centrally, and is not a central modulator of cardiorespiratory function and physiological reflexes.
    Autonomic neuroscience: basic & clinical 09/2011; 166(1-2):22-8. DOI:10.1016/j.autneu.2011.08.023 · 1.56 Impact Factor
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