The chromogranin A 1-373 fragment reveals how a single change in the protein sequence exerts strong cardioregulatory effects by engaging neuropilin-1.

Autor: Rocca C; Laboratory of Cellular and Molecular Cardiovascular Patho-Physiology, Department of Biology, E. and E.S., University of Calabria, Rende, Italy., Grande F; Laboratory of Medicinal and Analytical Chemistry, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy., Granieri MC; Laboratory of Cellular and Molecular Cardiovascular Patho-Physiology, Department of Biology, E. and E.S., University of Calabria, Rende, Italy., Colombo B; Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy., De Bartolo A; Laboratory of Cellular and Molecular Cardiovascular Patho-Physiology, Department of Biology, E. and E.S., University of Calabria, Rende, Italy.; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy., Giordano F; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy., Rago V; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy., Amodio N; Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy., Tota B; Laboratory of Cellular and Molecular Cardiovascular Patho-Physiology, Department of Biology, E. and E.S., University of Calabria, Rende, Italy.; Laboratory of Organ and System Physiology, Department of Biology, E. and E.S., University of Calabria, Rende, Italy., Cerra MC; Laboratory of Organ and System Physiology, Department of Biology, E. and E.S., University of Calabria, Rende, Italy., Rizzuti B; CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, Rende, Italy., Corti A; Division of Experimental Oncology, Vita-Salute San Raffaele University-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy., Angelone T; Laboratory of Cellular and Molecular Cardiovascular Patho-Physiology, Department of Biology, E. and E.S., University of Calabria, Rende, Italy.; National Institute of Cardiovascular Research (INRC), Bologna, Italy., Pasqua T; Laboratory of Cellular and Molecular Cardiovascular Patho-Physiology, Department of Biology, E. and E.S., University of Calabria, Rende, Italy.; 'Fondazione Umberto Veronesi', Milan, Italy.
Jazyk: angličtina
Zdroj: Acta physiologica (Oxford, England) [Acta Physiol (Oxf)] 2021 Apr; Vol. 231 (4), pp. e13570. Date of Electronic Publication: 2020 Nov 01.
DOI: 10.1111/apha.13570
Abstrakt: Aim: 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.
(© 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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