Chromogranin-A: A Multifaceted Cardiovascular Role in Health and Disease

Abstract

Chromogranin A (CgA), a major component of the chromaffin granules, is co-stored and co-released with catecholamines. It is also expressed in extra-adrenal sites, including the heart. In the rat, CgA localizes in atrial myoendocrine cells, associated with Atrial Natriuretic Peptide (ANP), and in the conduction system. In the human heart it is present in the ventricular myocardium, co-localized with B-type NP (BNP). CgA is the precursor of several biologically active peptides generated by proteolytic processing also in the heart. Two of them, vasostatin-1 (VS-1) and catestatin (Cst), inhibit cardiac contraction and relaxation, counter-regulate beta-adrenergic and endothelinergic stimulation, and protect the heart against ischemia/reperfusion damages. Recently, clinical studies have suggested CgA to be involved also in cardiovascular pathologies. High plasma CgA levels were found in hypertension, chronic and acute heart failure, myocardial infarction, decompensated and hypertrophic heart, and acute coronary syndromes. These alterations correlate with those of conventional cardiovascular biomarkers, such as NP and endothelin-1 (ET-1), and have prognostic relevance, being indicative of both severity of the disease and mortality. Accordingly, the current knowledge indicates CgA as a multifaceted peptide in cardiovascular homeostasis. Whether the influence elicited by the protein on both normal and failing heart is beneficial and/or detrimental, as well as its implication in the cardiac neuroendocrine scenario is under intense investigation. This review will focus on: i) the involvement of CgA and its derived peptides in the mechanisms which sustain cardiac function and compensation, ii) CgA clinical relevance, and iii) its putative value as a clinical biomarker.

Glycosylated Chromogranin A in Heart Failure

“…We found reduced CgA-to-CST conversion to be associated with a poor outcome in acute HF, but not in patients with acute exacerbation of COPD, which supports a role for CST in cardiomyocyte pathophysiology. Based on our data of CST as a CaMKII inhibitor and previous data that found CST to reduce myocardial ischemia-reperfusion injury, 12 increase cardiomyocyte cell survival, 25 and attenuate myocardial β-adrenergic and endothelin-1 signaling, 26 CST seems to be a counter-regulatory paracrine ligand of relevance in CVD. Given the paramount importance of hyperactive CaMKIIδ signaling in CVD, 16 the primary role of CST may be as part of a paracrine/autocrine protective feedback loop that could antagonize overactive myocardial CaMKIIδ signaling.…”

“…has been found to reduce myocardial β-adrenergic and endothelin-1 signaling, to affect myocardial contractility, to attenuate myocardial ischemia-reperfusion injury, 12 and to have a direct effect on Ca 2+ handling by interaction with calmodulin (CaM) in noncardiac cells. 13 However, currently no information is available in the literature concerning the processing of CgA to shorter peptide fragments in HF.…”

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

“…Actually, CST is known to counteract exaggerated β-adrenergic activity, which is relevant part of the neuroendocrine scenario of heart failure [1][2][3][4], and to dilate human vessels in vivo [16], thus exerting positive effects on cardiac afterload. In line with these evidences and since β-blockade is largely used as post-ischaemic treatment, the present work suggests that exogenous CST may provide new tool for pharmacological postconditioning.…”

“…In particular, in concert with mitoK ATP channels, the intramitochondrial protein kinase Cε (PKCε) activation may take part to the so-called "memory-associated protection". Nevertheless, the signal transduction pathways for protection from lethal and non-lethal reperfusion injury are still under intense debate [2,7,9,15,18,34].…”

“…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].…”