The novel chromogranin A‐derived serpinin and pyroglutaminated serpinin peptides are positive cardiac β‐adrenergic‐like inotropes

Abstract

Three forms of serpinin peptides, serpinin (Ala26Leu), pyroglutaminated (pGlu)-serpinin (pGlu23Leu), and serpinin-Arg-Arg-Gly (Ala29Gly), are derived from cleavage at pairs of basic residues in the highly conserved C terminus of chromogranin A (CgA). Serpinin induces PN-1 expression in neuroendocrine cells to up-regulate granule biogenesis via a cAMP-protein kinase A-Sp1 pathway, while pGlu-serpinin inhibits cell death. The aim of this study was to test the hypothesis that serpinin peptides are produced in the heart and act as novel β-adrenergic-like cardiac modulators. We detected serpinin peptides in the rat heart by HPLC and ELISA methods. The peptides included predominantly Ala29Gly and pGlu-serpinin and a small amount of serpinin. Using the Langendorff perfused rat heart to evaluate the hemodynamic changes, we found that serpinin and pGlu-serpinin exert dose-dependent positive inotropic and lusitropic effects at 11-165 nM, within the first 5 min after administration. The pGlu-serpinin-induced contractility is more potent than that of serpinin, starting from 1 nM. Using the isolated rat papillary muscle preparation to measure contractility in terms of tension development and muscle length, we further corroborated the pGlu-serpinin-induced positive inotropism. Ala29Gly was unable to affect myocardial performance. Both pGlu-serpinin and serpinin act through a β1-adrenergic receptor/adenylate cyclase/cAMP/PKA pathway, indicating that, contrary to the β-blocking profile of the other CgA-derived cardiosuppressive peptides, vasostatin-1 and catestatin, these two C-terminal peptides act as β-adrenergic-like agonists. In cardiac tissue extracts, pGlu-serpinin increased intracellular cAMP levels and phosphorylation of phospholamban (PLN)Ser16, ERK1/2, and GSK-3β. Serpinin and pGlu-serpinin peptides emerge as novel β-adrenergic inotropic and lusitropic modulators, suggesting that CgA and the other derived cardioactive peptides can play a key role in how the myocardium orchestrates its complex response to sympathochromaffin stimulation.

Chromofungin, CgA47-66-derived peptide, produces basal cardiac effects and postconditioning cardioprotective action during ischemia/reperfusion injury

“…The results on the Chr-induced modulation of the cardiac performance extend the knowledge on the regulatory influence elicited by circulating CGA and its fragments (VS-1, CST and serpinin) on the mammalian cardiocirculatory system [37,38]. Nothing is known on how these actions, as well as the proteolytic events which generate CGA fragments, are spatiotemporally coordinated.…”

“…They are generated by proteolytic cleavage not only in secretory vesicles of chromaffin cells, the main site for CgA synthesis and release, but also in extramedullary sites, including the heart [13,28]. CgA-derived peptides include the N-terminal vasostatin-1 (CgA1-76; VS-1), catestatin (CgA352-372; CTS), and the C-terminal serpinin (Serp) [7,5,3,38]. All of them elicit direct effects on the rat heart.…”

“…Moreover, by recruiting the reperfusion-injury-salvage-kinases (RISK)-pathway, both peptides elicit cardioprotection acting as pharmacological pre-conditioning (VS-1) and post-conditioning (CTS) agents [5,35]. Recently, the cardiac relevance of CgA and its fragments has been further supported by the characterization of the cardiostimulatory, beta1-adrenergic-like properties of Serp and the cardiodepressant activity of the full lenght CgA [38,28].…”

A kromograninok, szekretograninok élettani, kórélettani és klinikai szerepéről

“…A pozitív inotrop és lusitrop effektus jelentősen javítja a mechanikus kardiális teljesítményt; növekszik a szisztolés kamrai volumen, rövidül a diasztolés idő, továbbá tachycardiatendencia érvényesül és tágulnak az arteria coronariák. Ál-latkísérletben mutatkozik meg az intracardialis autokrin, parakrin hatásbeli út (ChrgrA-proteolysis, serpininkép-ződés, szívizomhatás, kardiális teljesítmény növekedése) [41][42][43][44]. Az eredmény szinte teljesen ellentétes a katesztatin-és vazosztatinhatásokkal.…”

Chromogranin A: a paradoxical player in angiogenesis and vascular biology

“…Remarkably, also the CgA fragments can work as cardio-regulatory hormones, in certain cases with opposite functions. While, full-length CgA, vasostatin-1 and catestatin depress myocardial contractility and relaxation, counteract the b-adrenergic-induced positive inotropism, and modulate coronary tone (via a nitric oxidedependent mechanism) [16], a fragment corresponding to the C-terminal region CgA 411-436 , called serpinin, enhances myocardial contractility and relaxation (via a b-adrenergic-cAMP-PKA and nitric oxide-independent pathway) [16,[34][35][36][37]. Analysis of the effluents from ex vivo perfused rat hearts showed that exogenous CgA was not cleaved by the heart, suggesting that the circulating, full-length protein can directly induce myocardial effects [16].…”