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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 4

GPAT4, AGPAT3, and AGPAT5 contribute to SFA-induced mineralization and ER stress of VSMCs.

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GPAT4, AGPAT3, and AGPAT5 contribute to SFA-induced mineralization and E...
ShRNA-mediated knockdown of acyltransferases in VSMCs. MOVAS-1 cells were infected with lentiviruses containing acyltransferase shRNAs for 48 hours and selected with 5 μg/ml puromycin to generate each acyltransferase stable knockdown VSMC. Levels of acyltransferase mRNAs were determined by qPCR. Each shRNA reduced its targeted acyltransferase by over 75%. (A) Mineralization of VSMCs in the presence of 18:0. The stable acyltransferase knockdown VSMCs were treated with 200 μM 18:0 as BSA complex for 7 days in the presence of 2 mM inorganic phosphate. (B) Levels of Chop mRNA in acyltransferase stable knockdown VSMCs treated with 200 μM 18:0. The stable acyltransferase knockdown VSMCs were treated with 200 μM 18:0 as BSA complex for 24 hours. Levels of Chop mRNA were analyzed by qPCR. **P < 0.001 vs. MOVAS-1 cells treated with empty shRNA and vehicle. n = 4; #P < 0.01 and ##P < 0.001 vs. MOVAS-1 cells treated with empty shRNA and 200 μM 18:0 (one-way ANOVA).
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