Myocardin related transcription factor and galectin-3 drive lipid accumulation in human blood vessels.

Autor: Arévalo-Martinez M; Molecular Vascular Physiology, Department of Experimental Medical Science, BMC D12, Lund University, SE-221 84 Lund, Sweden., Ede J; Department of Clinical Sciences Lund, Department of Cardiothoracic Surgery, Lund University, Skåne University Hospital, Lund, Sweden., van der Have O; Vessel Wall Biology, Department of Experimental Medical Science, BMC D12, Lund University, SE-221 84 Lund, Sweden., Ritsvall O; Molecular Vascular Physiology, Department of Experimental Medical Science, BMC D12, Lund University, SE-221 84 Lund, Sweden., Zetterberg FR; Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46 Lund, Sweden., Nilsson UJ; Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8 A, SE-413 46 Lund, Sweden; Department of Chemistry, Lund University, SE-221 00 Lund, Sweden., Leffler H; Department of Laboratory Medicine, Section MIG, Lund University BMC-C1228b, Klinikgatan 28, 221 84 Lund, Sweden., Holmberg J; Molecular Vascular Physiology, Department of Experimental Medical Science, BMC D12, Lund University, SE-221 84 Lund, Sweden., Albinsson S; Molecular Vascular Physiology, Department of Experimental Medical Science, BMC D12, Lund University, SE-221 84 Lund, Sweden. Electronic address: sebastian.albinsson@med.lu.se.
Jazyk: angličtina
Zdroj: Vascular pharmacology [Vascul Pharmacol] 2024 Sep; Vol. 156, pp. 107383. Date of Electronic Publication: 2024 Jun 01.
DOI: 10.1016/j.vph.2024.107383
Abstrakt: Objective: Diabetes and hypertension are important risk factors for vascular disease, including atherosclerosis. A driving factor in this process is lipid accumulation in smooth muscle cells of the vascular wall. The glucose- and mechano-sensitive transcriptional coactivator, myocardin-related transcription factor A (MRTF-A/MKL1) can promote lipid accumulation in cultured human smooth muscle cells and contribute to the formation of smooth muscle-derived foam cells. The purpose of this study was to determine if intact human blood vessels ex vivo can be used to evaluate lipid accumulation in the vascular wall, and if this process is dependent on MRTF and/or galectin-3/LGALS3. Galectin-3 is an early marker of smooth muscle transdifferentiation and a potential mediator for foam cell formation and atherosclerosis.
Approach and Results: Human mammary arteries and saphenous veins were exposed to altered cholesterol and glucose levels in an organ culture model. Accumulation of lipids, quantified by Oil Red O, was increased by cholesterol loading and elevated glucose concentrations. Pharmacological inhibition of MRTF with CCG-203971 decreased lipid accumulation, whereas adenoviral-mediated overexpression of MRTF-A had the opposite effect. Cholesterol-induced expression of galectin-3 was decreased after inhibition of MRTF. Importantly, pharmacological inhibition of galectin-3 with GB1107 reduced lipid accumulation in the vascular wall after cholesterol loading.
Conclusion: Ex vivo organ culture of human arteries and veins can be used to evaluate lipid accumulation in the intact vascular wall, as well as adenoviral transduction and pharmacological inhibition. Although MRTF and galectin-3 may have beneficial, anti-inflammatory effects under certain circumstances, our results, which demonstrate a significant decrease in lipid accumulation, support further evaluation of MRTF- and galectin-3-inhibitors for therapeutic intervention against atherosclerotic vascular disease.
Competing Interests: Declaration of competing interest The authors (MAM, JE, OH, OR and JH) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author (SA) is an Editorial Board Member for Vascular Pharmacology and was not involved in the editorial review or the decision to publish this article. The authors (UN, FLZ, and HL) declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors (UN, FLZ, and HL) are shareholders and consultants with Galecto Biotech AB, a company developing small molecule galectin inhibitors for treatments of fibrosis and cancer.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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