Selective inhibition of plasma membrane calcium ATPase 4 improves angiogenesis and vascular reperfusion.

Autor: Kurusamy S; Cardiovascular Molecular Pharmacology Laboratory, School of Pharmacy, University of Wolverhampton, Wolverhampton, UK., López-Maderuelo D; Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBERCV, Spain., Little R; Division of Cardiovascular Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK., Cadagan D; Cardiovascular Molecular Pharmacology Laboratory, School of Pharmacy, University of Wolverhampton, Wolverhampton, UK., Savage AM; Department of Infection, Immunity & Cardiovascular Disease & Bateson Centre, University of Sheffield, UK., Ihugba JC; Cardiovascular Molecular Pharmacology Laboratory, School of Pharmacy, University of Wolverhampton, Wolverhampton, UK., Baggott RR; Cardiovascular Molecular Pharmacology Laboratory, School of Pharmacy, University of Wolverhampton, Wolverhampton, UK., Rowther FB; Brain Tumor UK Neuro-oncology Research Centre, University of Wolverhampton, Wolverhampton, UK., Martínez-Martínez S; Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBERCV, Spain., Arco PG; Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBERCV, Spain; Department of Molecular Biology, Universidad Autonoma de Madrid (C.B.M.S.O.), Madrid, Spain., Murcott C; Cardiovascular Molecular Pharmacology Laboratory, School of Pharmacy, University of Wolverhampton, Wolverhampton, UK., Wang W; Oncology Laboratory, Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK., Francisco Nistal J; Cardiovascular Surgery, Hospital Universitario Marqués de Valdecilla, IDIVAL, Facultad de Medicina, Universidad de Cantabria, Santander, Spain., Oceandy D; Division of Cardiovascular Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK., Neyses L; Division of Cardiovascular Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK; University of Luxembourg, Luxembourg., Wilkinson RN; Department of Infection, Immunity & Cardiovascular Disease & Bateson Centre, University of Sheffield, UK., Cartwright EJ; Division of Cardiovascular Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK., Redondo JM; Gene Regulation in Cardiovascular Remodelling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBERCV, Spain. Electronic address: jmredondo@cnic.es., Armesilla AL; Cardiovascular Molecular Pharmacology Laboratory, School of Pharmacy, University of Wolverhampton, Wolverhampton, UK; CIBERCV, Spain. Electronic address: A.Armesilla@wlv.ac.uk.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2017 Aug; Vol. 109, pp. 38-47. Date of Electronic Publication: 2017 Jul 03.
DOI: 10.1016/j.yjmcc.2017.07.001
Abstrakt: Aims: Ischaemic cardiovascular disease is a major cause of morbidity and mortality worldwide. Despite promising results from pre-clinical animal models, VEGF-based strategies for therapeutic angiogenesis have yet to achieve successful reperfusion of ischaemic tissues in patients. Failure to restore efficient VEGF activity in the ischaemic organ remains a major problem in current pro-angiogenic therapeutic approaches. Plasma membrane calcium ATPase 4 (PMCA4) negatively regulates VEGF-activated angiogenesis via inhibition of the calcineurin/NFAT signalling pathway. PMCA4 activity is inhibited by the small molecule aurintricarboxylic acid (ATA). We hypothesize that inhibition of PMCA4 with ATA might enhance VEGF-induced angiogenesis.
Methods and Results: We show that inhibition of PMCA4 with ATA in endothelial cells triggers a marked increase in VEGF-activated calcineurin/NFAT signalling that translates into a strong increase in endothelial cell motility and blood vessel formation. ATA enhances VEGF-induced calcineurin signalling by disrupting the interaction between PMCA4 and calcineurin at the endothelial-cell membrane. ATA concentrations at the nanomolar range, that efficiently inhibit PMCA4, had no deleterious effect on endothelial-cell viability or zebrafish embryonic development. However, high ATA concentrations at the micromolar level impaired endothelial cell viability and tubular morphogenesis, and were associated with toxicity in zebrafish embryos. In mice undergoing experimentally-induced hindlimb ischaemia, ATA treatment significantly increased the reperfusion of post-ischaemic limbs.
Conclusions: Our study provides evidence for the therapeutic potential of targeting PMCA4 to improve VEGF-based pro-angiogenic interventions. This goal will require the development of refined, highly selective versions of ATA, or the identification of novel PMCA4 inhibitors.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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