The surging role of Chromogranin A in cardiovascular homeostasis

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.

Keywords: Catestatin; Chromogranin A; Serpinin; Vasostatin 1; adreno-sympathetic control; cardioprotection; endothelial signaling; vasoactive peptides.

Figure 1

This synopsis illustrates Chromogranin-A (CgA) processing and biological activities which are reviewed in this volume (modified from Angelone and Tota, 2012). This provides a cardiovascular dimension for CgA, with important outcomes in terms of biology, physiology and clinics.

Figure 2

Schematic representation of the possible sites for intervention of CgA and its derived peptides in heart failure. CgA and its fragments could operate at two, non-exclusive, levels: systemic and local. At the systemic level, CgA may work together with other factors (catecholamines, ANGII, cytochines, chemochines, etc) in the stress response, as in the case of the neuroendocrine scenario activated in CHF. At the local (heart) level, systemic and/or intracardiac physical and chemical stimuli could trigger CgA processing to generate cardioactive peptides, i.e., VSs, CST, serpinin (modified from Angelone et al., 2012a).

Figure 3

Representative scheme showing the physiological (A) and the physiopathological (B) (i.e., cardioprotection) pathways activated by CgA-derived peptides. Cardioinhibitory effects induced by VS1 and CST involve the NOS/NO/cGMP/PKG pathway. Serpinin-dependent positive inotropism involves the AD/cAMP/PKA pathway.

Figure 4

Representative picture showing the ability of CgA-derived peptides to reset cardio-circulatory homeostasis through “whip-brake” networks in response to perturbed conditions. A tissue-specific and spatio-temporally concerted processing of CGA can generate counter-regulatory peptides able to reset cardio-circulatory homeostasis through “whip-brake” networks.