Author(s):
Alves, Liliana S. ; Marques, André R. A. ; Padrão, Nuno ; Carvalho, Filomena A. ; Ramalho, José ; Lopes, Catarina S. ; Soares, Maria I. L. ; Futter, Clare E. ; Pinho e Melo, Teresa M. V. D. ; Santos, Nuno C. ; Vieira, Otília V.
Date: 2022
Persistent ID: https://hdl.handle.net/10316/107454
Origin: Estudo Geral - Universidade de Coimbra
Subject(s): Atherosclerosis; Lysosome adaptation; Lysosome dysfunction; Oxidized lipids; Vascular smooth muscle cell; Cell Proliferation; Cells, Cultured; Foam Cells; Homeostasis; Lysosomes; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle
Description
In atherosclerotic lesions, vascular smooth muscle cells (VSMCs) represent half of the foam cell population, which is characterized by an aberrant accumulation of undigested lipids within lysosomes. Loss of lysosome function impacts VSMC homeostasis and disease progression. Understanding the molecular mechanisms underlying lysosome dysfunction in these cells is, therefore, crucial. We identify cholesteryl hemiazelate (ChA), a stable oxidation end-product of cholesteryl-polyunsaturated fatty acid esters, as an inducer of lysosome malfunction in VSMCs. ChA-treated VSMCs acquire a foam-cell-like phenotype, characterized by enlarged lysosomes full of ChA and neutral lipids. The lysosomes are perinuclear and exhibit degradative capacity and cargo exit defects. Lysosome luminal pH is also altered. Even though the transcriptional response machinery and autophagy are not activated by ChA, the addition of recombinant lysosomal acid lipase (LAL) is able to rescue lysosome dysfunction. ChA significantly affects VSMC proliferation and migration, impacting atherosclerosis. In summary, this work shows that ChA is sufficient to induce lysosomal dysfunction in VSMCs, that, in ChA-treated VSMCs, neither lysosome biogenesis nor autophagy are triggered, and, finally, that recombinant LAL can be a therapeutic approach for lysosomal dysfunction.
This work was supported by Fundação para a Ciência e a Tecnologia, I.P (FCT, Portugal), projects 03/SAICT/2015, PTDC/EMD-TLM/7289/2020 and PTDC/MEDPAT/ 29395/2017, through national funds and co-funded by FEDER under the PT2020 Partnership. The Coimbra Chemistry Centre (CQC) is supported by FCT through project UID/QUI/00313/2019. This work was also supported by a European Commission Twinning on “Excel in Rare Diseases’ Research: Focus on LYSOsomal Disorders and CILiopathies’ grant (H2020-TWINN-2017: GA 81108). L.S.A. was a holder of a FCT PhD fellowship (PD/BD/114254/2016), attributed by the ProRegem Doctoral Programme in 2016. C.S.L. is also a holder of a FCT PhD fellowship (PD/ BD/135045/2017). A.R.A.M. was funded by the FCT Stimulus of Scientific Employment Individual Support Call 2017 (CEECIND/01006/2017).
