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Lysosome Dysfunction and Medial Calcification in the Arterial Wall of Smooth Muscle Cell‐Specific Smpd1 Transgenic Mice: A Ceramide‐Mediated Vasculopathy
Author(s) -
Bhat Owais M,
Yuan Xinxu,
Lohner Hannah,
Li PinLan
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.679.13
Subject(s) - lysosome , ceramide , osteopontin , sphingomyelin phosphodiesterase , acid sphingomyelinase , calcification , exosome , medicine , endocrinology , biology , microbiology and biotechnology , chemistry , biochemistry , microvesicles , apoptosis , microrna , gene , enzyme
It has been reported that multivesicular body (MVB) trafficking and release of exosomes are a hallmark of vascular calcification. Since ceramide is a crucial regulator of lysosome function, the present study was performed to test whether lysosomal acid sphingomyelinase (its mouse gene code is Smpd1 )‐derived ceramide contributes to the exosome secretion from smooth muscle cells (SMCs) and consequently lead to arterial calcification. In Smpd1 trg /SM cre mice with SMC‐specific overexpression of Smpd1 gene, a high dose of Vit D (500,000 IU/kg/day) induced much more aortic and coronary arterial medial calcification compared to their littermates ( Smpd1 fl/fl /WT and WT/WT mice), as detected by Alizarin Red S and Von Kossa staining. It was also found that there was more significantly increased expression of RUNX2 and osteopontin in the coronary and aortic media of Smpd1 trg /SM cre mice than their littermates, indicating a SMC phenotypic transition to osteogenic in these SMC‐specific Smpd1 transgenic mice. When these mice received treatment with amitriptyline, an Asm inhibitor, the calcification and phenotypic switch in both coronary and aortic medial SMCs were reversed. Furthermore, Smpd1 trg /SM cre mice were found to have increased annexin 2 (AnX2) and alkaline phosphatase (ALP) levels (exosome markers) in the arterial wall, which was accompanied by reduced co‐localization of lysosome marker (LAMP‐1) with MVB marker (VPS16), a parameter for lysosome‐MVB interaction. All these changes related to lysosome function and exosome release from SMCs in Smpd1 trg /SM cre mice were substantially attenuated by amitriptyline treatment. These data indicate that lysosomal ceramide plays a critical role in phenotype change and exosome release in SMCs, which may contribute to the control of mineral metabolism or deposition in the arterial wall. Support or Funding Information Supported by NIH grants HL057244, HL075316 and DK120491 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .