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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

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 2

Generation of SMC-Scd1/2 KO mice.

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Generation of SMC-Scd1/2 KO mice.
(A) Levels of Scd1 and Scd2 mRNA in th...
(A) Levels of Scd1 and Scd2 mRNA in the medial layer of aortas of SMC-Scd1/2 KO mice and control mice (n = 8). Scd1 and Scd2 RNA expression was determined by qPCR. (B) Immunoblot analysis of SCD1 and SCD2 proteins. Total protein extracts were prepared from the medial layer of the aortas and subjected to immunoblot analysis with SCD1- and SCD2-specific antibodies. (C) Microsomal SCD activity in the medial layer of aortas. Microsomal protein (100 μg) was incubated with 14C-18:0-CoA in the presence of NADH. SCD activity was determined as the conversion of 18:0-CoA to 18:1n-9. (D) Fatty acid content in the medial layer of aortas from SMC-Scd1/2 KO mice and control mice. **P < 0.001 vs. control mice (2-tailed Student’s t test).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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