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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 7

Fully unsaturated, but not partially saturated or fully saturated PAs, induce mineralization, osteogenic differentiation, and ER stress.

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Fully unsaturated, but not partially saturated or fully saturated PAs, i...
(A) Fully saturated PAs are disfavor substrates for LIPIN2. The lysate of HEK293 cells infected with adenovirus containing human LIPIN2 was used as a LIPIN2 recombinant protein. LIPIN2 activity was measured as the conversion of PA to DAG using LC-MS/MS. The fully saturated PAs 18:0/18:0-PA and 16:0/16:0-PA)but not the partially saturated PAs 18:0/18:1-PA and 16:0/18:1-PA or the fully unsaturated PAs 18:1/18:1-PA and 18:2/18:2-PA dose-dependently induced (B–D) mineralization and (E–G) osteogenic differentiation of VSMCs. VSMCs were treated with each PA for 7 days in the presence of 2.0 mM phosphate. (B) Seven days after the treatments, the cells treated with PAs (20 μM) were stained with Alizarin red to identify calcium deposits. (C and D) Calcium was extracted with 0.6 N hydrochloric acid and analyzed using a colorimetric assay. (E–G) Ocn, Opn, and PiT1 were quantified by qPCR. (H–J) Fully saturated PAs such as 18:0/18:0-PA, but not fully unsaturated PAs such as 18:1/18:1-PA, induce ER stress. VSMCs were treated with 10 μM PAs for 6 and 24 hours. Total protein extracts were subjected to immunoblot analysis with ATF4- and CHOP-specific antibodies. Atf4 and Chop mRNA levels were quantified by qPCR. (K) 18:0/18:0-PA induces mineralization of VSMCs through the activation of the ATF4-CHOP axis of the ER stress response. Atf4 and Chop knockdown MOVAS cells were treated with 10 μM 18:0/18:0-PA for 7 days. n = 6; *P < 0.05 (one-way ANOVA).

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

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