Myocardial production of chromogranin A in human heart: a new regulatory peptide of cardiac function

Pieroni, Maurizio; Corti, Angelo; Tota, Bruno; Curnis, Flavio; Angelone, Tommaso; Colombo, Barbara; Cerra, Maria Carmela; Bellocci, Fulvio; Crea, Filippo; Maseri, Attilio

doi:10.1093/eurheartj/ehm022

Cited by 155 publications

(164 citation statements)

References 25 publications

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“…The cardiac activity of CST is achieved through signalling pathways expected for receptor-orphan peptides with membraneinteracting properties [4]. Here, using classic antagonists [14,35,39,[41][42][43][44], we demonstrated for the first time that the cardioprotective effect of CST-Post depends on the activation of PI3k/Akt, PKCs and of mitoK ATP channels, which may include a ROS signalling. The prevention of mPTP opening in myocytes challenged with oxidative stress reinforces the idea that CST protective effects converge on mitochondria.…”

Section: Discussionmentioning

confidence: 91%

“…Recently, several biologically active peptides derived from chromogranin A (CgA), including Vasostatin-1 (VS-1) and Catestatin (CST), have received attention as regulators of cardiovascular function [2,11,12,19,22,29,43]. For instance, the N-terminal VS-1 induced a preconditioning-like effect via adenosine/nitric oxide (NO) protective signalling, reducing the extension of myocardial infarction in the rat heart [10].…”

Section: Introductionmentioning

confidence: 99%

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Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Perrelli

Tullio

Angotti

et al. 2013

Pflugers Arch - Eur J Physiol

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Aims: 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 (mitoK ATP ) channels and subsequent reactiveoxygen-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. Methods and Results: 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 CSTinduced 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 H 2 O 2 , mitochondrialdepolarization (an index of mPTP-opening studied with JC1-probe) was drastically limited by CST (75nM). Conclusions: Our results suggest that the protective signalling pathway activated by CST includes mitoK ATP 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 mitoK ATP 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.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Perrelli

Tullio

Angotti

et al. 2013

Pflugers Arch - Eur J Physiol

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“…Under normal conditions, CgA is expressed at low levels, only detectable by PCR and ELISA, but in the presence of dilated and hypertrophic cardiomyopathy, the peptide is also immunologically detectable on tissue sections (Pieroni et al, 2007). Importantly, in the heart, CgA correlates with the cardiac NP system, since in atrial myocytes and in the conduction cells, it is co-stored with ANP, while in the ventricle it co-localizes with BNP (Pieroni et al, 2007) (Fig. 4).…”

Section: Qkkhsgfedelsevlenqssqaelkeaveepsskdvmekrmentioning

confidence: 99%

“…Detected since 1990 in the granules of rat atrial myoendocrine cells (Steiner et al, 1990) and in the cells of the cardiac conduction system co-localized with the a1E subunit of the voltage-gated calcium channel (Weiergraber et al, 2000), CgA was identified more recently in the human ventricular myocardium (Pieroni et al, 2007). Under normal conditions, CgA is expressed at low levels, only detectable by PCR and ELISA, but in the presence of dilated and hypertrophic cardiomyopathy, the peptide is also immunologically detectable on tissue sections (Pieroni et al, 2007). Importantly, in the heart, CgA correlates with the cardiac NP system, since in atrial myocytes and in the conduction cells, it is co-stored with ANP, while in the ventricle it co-localizes with BNP (Pieroni et al, 2007) (Fig.…”

Section: Qkkhsgfedelsevlenqssqaelkeaveepsskdvmekrmentioning

confidence: 99%

Catecholamines, cardiac natriuretic peptides and chromogranin A: evolution and physiopathology of a ‘whip-brake’ system of the endocrine heart

Tota

Cerra

Gattuso

2010

Journal of Experimental Biology

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Summary In the past 50 years, extensive evidence has shown the ability of vertebrate cardiac non-neuronal cells to synthesize and release catecholamines (CA). This formed the mindset behind the search for the intrinsic endocrine heart properties, culminating in 1981 with the discovery of the natriuretic peptides (NP). CA and NP, co-existing in the endocrine secretion granules and acting as major cardiovascular regulators in health and disease, have become of great biomedical relevance for their potent diagnostic and therapeutic use. The concept of the endocrine heart was later enriched by the identification of a growing number of cardiac hormonal substances involved in organ modulation under normal and stress-induced conditions. Recently, chromogranin A (CgA), a major constituent of the secretory granules, and its derived cardio-suppressive and antiadrenergic peptides, vasostatin-1 and catestatin, were shown as new players in this framework, functioning as cardiac counter-regulators in ‘zero steady-state error’ homeostasis, particularly under intense excitatory stimuli, e.g. CA-induced myocardial stress. Here, we present evidence for the hypothesis that is gaining support, particularly among human cardiologists. The actions of CA, NP and CgA, we argue, may be viewed as a hallmark of the cardiac capacity to organize ‘whip-brake’ connection-integration processes in spatio-temporal networks. The involvement of the nitric oxide synthase (NOS)/nitric oxide (NO) system in this configuration is discussed. The use of fish and amphibian paradigms will illustrate the ways that incipient endocrine-humoral agents have evolved as components of cardiac molecular loops and important intermediates during evolutionary transitions, or in a distinct phylogenetic lineage, or under stress challenges. This may help to grasp the old evolutionary roots of these intracardiac endocrine/paracrine networks and how they have evolved from relatively less complicated designs. The latter can also be used as an intellectual tool to disentangle the experimental complexity of the mammalian and human endocrine hearts, suggesting future investigational avenues.

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“…Vasostatins exert a negative inotropic effect on isolated frog and eel hearts and counteract the actions of -adrenergic drugs [68,69]. BNP and CGA are co-stored in the myocardium of patients with dilated cardiomyopathy, whereas this co-localisation was not found in healthy controls [70]. We investigated the expression of natriuretic peptides (NP) and CGA by immunohistochemistry and morphometric quantification before and after LVAD.…”

Section: Natriuretic Peptides and Chromogranin Amentioning

confidence: 99%

Morphological and molecular changes of the myocardium after left ventricular mechanical support

Baba

Wohlschlaeger

2008

Journal of Molecular and Cellular Cardiology

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Myocardial production of chromogranin A in human heart: a new regulatory peptide of cardiac function

Abstract: We demonstrate for the first time that CgA is produced by human myocardium and exerts negative inotropic and lusitropic effects on mammalian heart. CgA may represent a key player in neuroendocrine regulation of cardiac function and a potential therapeutic target in heart failure.

Cited by 155 publications

References 25 publications

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Catecholamines, cardiac natriuretic peptides and chromogranin A: evolution and physiopathology of a ‘whip-brake’ system of the endocrine heart

Morphological and molecular changes of the myocardium after left ventricular mechanical support

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