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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4544-4558
Number of pages15
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
StatePublished - Dec 1 2015

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Vascular Calcification
Phosphatidic Acids
Fatty Acids
Stearoyl-CoA Desaturase
Metabolic Diseases
Vascular Smooth Muscle
Small Interfering RNA
Smooth Muscle Myocytes
Cardiovascular Diseases
Enzymes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Masuda, M., Miyazaki-Anzai, S., Keenan, A. L., Okamura, K., Kendrick, J., Chonchol, M., ... Miyazaki, M. (2015). Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity. Journal of Clinical Investigation, 125(12), 4544-4558. https://doi.org/10.1172/JCI82871

Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity. / Masuda, Masashi; Miyazaki-Anzai, Shinobu; Keenan, Audrey L.; Okamura, Kayo; Kendrick, Jessica; Chonchol, Michel; Offermanns, Stefan; Ntambi, James M.; Kuro-O, Makoto; Miyazaki, Makoto.

In: Journal of Clinical Investigation, Vol. 125, No. 12, 01.12.2015, p. 4544-4558.

Research output: Contribution to journalArticle

Masuda, M, Miyazaki-Anzai, S, Keenan, AL, Okamura, K, Kendrick, J, Chonchol, M, Offermanns, S, Ntambi, JM, Kuro-O, M & Miyazaki, M 2015, 'Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity', Journal of Clinical Investigation, vol. 125, no. 12, pp. 4544-4558. https://doi.org/10.1172/JCI82871
Masuda M, Miyazaki-Anzai S, Keenan AL, Okamura K, Kendrick J, Chonchol M et al. Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity. Journal of Clinical Investigation. 2015 Dec 1;125(12):4544-4558. https://doi.org/10.1172/JCI82871
Masuda, Masashi ; Miyazaki-Anzai, Shinobu ; Keenan, Audrey L. ; Okamura, Kayo ; Kendrick, Jessica ; Chonchol, Michel ; Offermanns, Stefan ; Ntambi, James M. ; Kuro-O, Makoto ; Miyazaki, Makoto. / Saturated phosphatidic acids mediate saturated fatty acid-induced vascular calcification and lipotoxicity. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 12. pp. 4544-4558.
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