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Saturated phosphatidic acids mediate saturated fatty acid–induced vascular calcification and lipotoxicity
Masashi Masuda, … , Makoto Kuro-o, Makoto Miyazaki
Masashi Masuda, … , Makoto Kuro-o, Makoto Miyazaki
Published October 26, 2015
Citation Information: J Clin Invest. 2015;125(12):4544-4558. https://doi.org/10.1172/JCI82871.
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Research Article Vascular biology Article has an altmetric score of 2

Saturated phosphatidic acids mediate saturated fatty acid–induced vascular calcification and lipotoxicity

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Abstract

Recent evidence indicates that saturated fatty acid–induced (SFA-induced) lipotoxicity contributes to the pathogenesis of cardiovascular and metabolic diseases; however, the molecular mechanisms that underlie SFA-induced lipotoxicity remain unclear. Here, we have shown that repression of stearoyl-CoA desaturase (SCD) enzymes, which regulate the intracellular balance of SFAs and unsaturated FAs, and the subsequent accumulation of SFAs in vascular smooth muscle cells (VSMCs), are characteristic events in the development of vascular calcification. We evaluated whether SMC-specific inhibition of SCD and the resulting SFA accumulation plays a causative role in the pathogenesis of vascular calcification and generated mice with SMC-specific deletion of both Scd1 and Scd2. Mice lacking both SCD1 and SCD2 in SMCs displayed severe vascular calcification with increased ER stress. Moreover, we employed shRNA library screening and radiolabeling approaches, as well as in vitro and in vivo lipidomic analysis, and determined that fully saturated phosphatidic acids such as 1,2-distearoyl-PA (18:0/18:0-PA) mediate SFA-induced lipotoxicity and vascular calcification. Together, these results identify a key lipogenic pathway in SMCs that mediates vascular calcification.

Authors

Masashi Masuda, Shinobu Miyazaki-Anzai, Audrey L. Keenan, Kayo Okamura, Jessica Kendrick, Michel Chonchol, Stefan Offermanns, James M. Ntambi, Makoto Kuro-o, Makoto Miyazaki

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Figure 3

SMC-specific SCD1 and SCD2 double deficiency induces vascular calcification, ER stress, and vascular apoptosis.

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SMC-specific SCD1 and SCD2 double deficiency induces vascular calcificat...
(A) Representative photograph (×10) of the lesions of aortic sinuses stained with von Kossa. Mice (n = 8) were sacrificed after 10 weeks of tamoxifen injections. Quantitative analysis of calcified lesions in the (B) aortic sinus and (C) aortic arch. (D) Aortic calcium content in SMC-Scd1/2 KO mice. (E) mRNA levels of ER stress, osteogenic differentiation, and SMC markers in VSMCs. VSMCs were isolated by immunomagnetic cell sorting. Scd1 and Scd2 mRNA expression was determined by qPCR. (F) Immunoblot analysis of ATF4 and CHOP protein expression in the medial layer of aortas of SMC-Scd1/2 KO mice. (G) Representative micrographs show more TUNEL+ signal (red) in nuclei (blue) of aortic sinus lesions from control and SMC-Scd1/2 KO mice. (H) Quantitative analysis of TUNEL+ nuclei conducted on lesions from SMC-Scd1/2 KO mice. (I) Immunofluorescence analysis of CHOP in the aortic sinuses of SMC-Scd1/2 KO mice. *P < 0.01 and **P < 0.001 vs. control mice (2-tailed Student’s t test).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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