In:
Acta Physiologica, Wiley, Vol. 231, No. 4 ( 2021-04)
Abstract:
Chromogranin A (CgA), a 439‐residue long protein, is an important cardiovascular regulator and a precursor of various bioactive fragments. Under stressful/pathological conditions, CgA cleavage generates the CgA 1‐373 proangiogenic fragment. The present work investigated the possibility that human CgA 1‐373 influences the mammalian cardiac performance, evaluating the role of its C‐terminal sequence. Methods Haemodynamic assessment was performed on an ex vivo Langendorff rat heart model, while mechanistic studies were performed using perfused hearts, H9c2 cardiomyocytes and in silico. Results On the ex vivo heart, CgA 1‐373 elicited direct dose‐dependent negative inotropism and vasodilation, while CgA 1‐372 , a fragment lacking the C‐terminal R 373 residue, was ineffective. Antibodies against the PGPQLR 373 C‐terminal sequence abrogated the CgA 1‐373 ‐dependent cardiac and coronary modulation. Ex vivo studies showed that CgA 1‐373 ‐dependent effects were mediated by endothelium, neuropilin‐1 (NRP1) receptor, Akt/NO/Erk1,2 pathways, nitric oxide (NO) production and S‐nitrosylation. In vitro experiments on H9c2 cardiomyocytes indicated that CgA 1‐373 also induced eNOS activation directly on the cardiomyocyte component by NRP1 targeting and NO involvement and provided beneficial action against isoproterenol‐induced hypertrophy, by reducing the increase in cell surface area and brain natriuretic peptide (BNP) release. Molecular docking and all‐atom molecular dynamics simulations strongly supported the hypothesis that the C‐terminal R 373 residue of CgA 1‐373 directly interacts with NRP1. Conclusion These results suggest that CgA 1‐373 is a new cardioregulatory hormone and that the removal of R 373 represents a critical switch for turning “off” its cardioregulatory activity.
Type of Medium:
Online Resource
ISSN:
1748-1708
,
1748-1716
DOI:
10.1111/apha.2021.231.issue-4
Language:
English
Publisher:
Wiley
Publication Date:
2021
detail.hit.zdb_id:
2617148-X
detail.hit.zdb_id:
2219379-0
SSG:
12
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