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Medial calcification in the arterial wall of smooth muscle cell-specific Smpd1 transgenic mice: A ceramide-mediated vasculopathy.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2020 Jan; Vol. 24 (1), pp. 539-553. Date of Electronic Publication: 2019 Nov 19. - Publication Year :
- 2020
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Abstract
- Arterial medial calcification (AMC) is associated with crystallization of hydroxyapatite in the extracellular matrix and arterial smooth muscle cells (SMCs) leading to reduced arterial compliance. The study was performed to test whether lysosomal acid sphingomyelinase (murine gene code: Smpd1)-derived ceramide contributes to the small extracellular vesicle (sEV) secretion from SMCs and consequently leads to AMC. In Smpd1 <superscript>trg</superscript> /SM <superscript>cre</superscript> mice with SMC-specific overexpression of Smpd1 gene, a high dose of Vit D (500 000 IU/kg/d) resulted in increased aortic and coronary AMC, associated with augmented expression of RUNX2 and osteopontin in the coronary and aortic media compared with their littermates (Smpd1 <superscript>trg</superscript> /SM <superscript>wt</superscript> and WT/WT mice), indicating phenotypic switch. However, amitriptyline, an acid sphingomyelinase (ASM) inhibitor, reduced calcification and reversed phenotypic switch. Smpd1 <superscript>trg</superscript> /SM <superscript>cre</superscript> mice showed increased CD63, AnX2 and ALP levels in the arterial wall, accompanied by reduced co-localization of lysosome marker (Lamp-1) with multivesicular body (MVB) marker (VPS16), a parameter for lysosome-MVB interaction. All these changes related to lysosome fusion and sEV release were substantially attenuated by amitriptyline. Increased arterial stiffness and elastin disorganization were found in Smpd1 <superscript>trg</superscript> /SM <superscript>cre</superscript> mice as compared to their littermates. In cultured coronary arterial SMCs (CASMCs) from Smpd1 <superscript>trg</superscript> /SM <superscript>cre</superscript> mice, increased P <subscript>i</subscript> concentrations led to markedly increased calcium deposition, phenotypic change and sEV secretion compared with WT CASMCs, accompanied by reduced lysosome-MVB interaction. However, amitriptyline prevented these changes in P <subscript>i</subscript> -treated CASMCs. These data indicate that lysosomal ceramide plays a critical role in phenotype change and sEV release in SMCs, which may contribute to the arterial stiffness during the development of AMC.<br /> (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Subjects :
- Animals
Aorta drug effects
Aorta pathology
Aorta physiopathology
Extracellular Vesicles drug effects
Extracellular Vesicles metabolism
Lysosomes drug effects
Lysosomes metabolism
Mice, Transgenic
Phenotype
Vascular Calcification physiopathology
Vascular Stiffness drug effects
Vitamin D pharmacology
Ceramides adverse effects
Coronary Vessels pathology
Myocytes, Smooth Muscle metabolism
Myocytes, Smooth Muscle pathology
Sphingomyelin Phosphodiesterase metabolism
Vascular Calcification pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 24
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 31743567
- Full Text :
- https://doi.org/10.1111/jcmm.14761