Fluorinated perhexiline derivative attenuates vascular proliferation in pulmonary arterial hypertension smooth muscle cells.

Autor: Griffiths K; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK., Grand RJ; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK., Horan I; Department for Medicine, University of Cambridge, Cambridge, UK., Certo M; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., Keeler RC; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK., Mauro C; Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., Tseng CC; Kosterlitz Centre for Therapeutics, University of Aberdeen, Aberdeen, UK., Greig I; Kosterlitz Centre for Therapeutics, University of Aberdeen, Aberdeen, UK., Morrell NW; Department for Medicine, University of Cambridge, Cambridge, UK., Zanda M; The Institute of Chemical Sciences and Technologies, Milan, Italy., Frenneaux MP; Academic Health System, Hamad Medical Corporation, Doha, Qatar., Madhani M; Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK. Electronic address: m.madhani@bham.ac.uk.
Jazyk: angličtina
Zdroj: Vascular pharmacology [Vascul Pharmacol] 2024 Sep; Vol. 156, pp. 107399. Date of Electronic Publication: 2024 Jun 18.
DOI: 10.1016/j.vph.2024.107399
Abstrakt: Increased proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs) is recognised as a universal hallmark of pulmonary arterial hypertension (PAH), in part related to the association with reduced pyruvate dehydrogenase (PDH) activity, resulting in decreased oxidative phosphorylation of glucose and increased aerobic glycolysis (Warburg effect). Perhexiline is a well-recognised carnitine palmitoyltransferase-1 (CPT1) inhibitor used in cardiac diseases, which reciprocally increases PDH activity, but is associated with variable pharmacokinetics related to polymorphic variation of the cytochrome P450-2D6 (CYP2D6) enzyme, resulting in the risk of neuro and hepatotoxicity in 'slow metabolisers' unless blood levels are monitored and dose adjusted. We have previously reported that a novel perhexiline fluorinated derivative (FPER-1) has the same therapeutic profile as perhexiline but is not metabolised by CYP2D6, resulting in more predictable pharmacokinetics than the parent drug. We sought to investigate the effects of perhexiline and FPER-1 on PDH flux in PASMCs from patients with PAH. We first confirmed that PAH PASMCs exhibited increased cell proliferation, enhanced phosphorylation of AKT Ser473 , ERK 1/2 Thr202/Tyr204 and PDH-E1α Ser293 , indicating a Warburg effect when compared to healthy PASMCs. Pre-treatment with perhexiline or FPER-1 significantly attenuated PAH PASMC proliferation in a concentration-dependent manner and suppressed the activation of the AKT Ser473 but had no effect on the ERK pathway. Perhexiline and FPER-1 markedly activated PDH (seen as dephosphorylation of PDH-E1α Ser293 ), reduced glycolysis, and upregulated mitochondrial respiration in these PAH PASMCs as detected by Seahorse analysis. However, both perhexiline and FPER-1 did not induce apoptosis as measured by caspase 3/7 activity. We show for the first time that both perhexiline and FPER-1 may represent therapeutic agents for reducing cell proliferation in human PAH PASMCs, by reversing Warburg physiology.
Competing Interests: Declaration of competing interest The authors declare that they have no competing interests.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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