Dataset Information

Carnitine O-octanoyltransferase is a novel inducer of vascular calcification via promoting fatty acid metabolism and mitochondrial dysfunction

ABSTRACT: Objective – Vascular calcification is a critical pathology associated with increased cardiovascular event risk, but there are no FDA-approved anti-calcific therapies. We hypothesized and validated that an unbiased screening approach would identify novel mediators of human vascular calcification. Approach and Results – We performed an unbiased quantitative proteomics and pathway network analysis that identified increased carnitine O-octanoyltransferase (CROT) in calcifying primary human coronary artery smooth muscle cells (SMCs). Additionally, human carotid artery atherosclerotic plaques contained increased immunoreactive CROT near calcified regions. CROT siRNA reduced fibrocalcific response in calcifying SMCs. In agreement, histidine 327 to alanine point mutation inactivated human CROT fatty acid metabolism enzymatic activity and suppressed SMC calcification. CROT siRNA restored mitochondrial proteome alterations and suppressed mitochondrial fragmentation in calcifying SMCs. Lipidomics analysis of SMCs incubated with CROT siRNA revealed increased eicosapentaenoic acid, a vascular calcification inhibitor. CRISPR/Cas9-mediated Crot deficiency in low-density lipoprotein receptor-deficient mice reduced aortic and carotid artery calcification without altering bone density, or liver and plasma cholesterol and triglyceride concentrations. Conclusions – CROT is a novel inducer of vascular calcification via promoting fatty acid metabolism and mitochondrial dysfunction, as such CROT inhibition has strong potential as an anti-fibrocalcific therapy.

INSTRUMENT(S): Orbitrap Fusion Lumos, LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Smooth Muscle Cell Of The Coronary Artery, Cell Culture, Coronary Artery Smooth Muscle Cell

SUBMITTER: Sasha Singh

LAB HEAD: Elena Aikawa

PROVIDER: PXD022575 | Pride | 2021-02-26

REPOSITORIES: Pride

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			Action	DRS
	02_MI_hCASMC-NM_D1_TMT-Fr-25_x10_LysC-TMT.raw	Raw
	02_MI_hCASMC-NM_D1_TMT-Fr-26_x10_LysC-TMT.raw	Raw
	02_MI_hCASMC-NM_D1_TMT-Fr-27_x10_LysC-TMT.raw	Raw
	02_MI_hCASMC-NM_D1_TMT-Fr-28_x10_LysC-TMT.raw	Raw
	02_MI_hCASMC-NM_D1_TMT-Fr-29_x10_LysC-TMT.raw	Raw

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Publications

CROT (Carnitine O-Octanoyltransferase) Is a Novel Contributing Factor in Vascular Calcification via Promoting Fatty Acid Metabolism and Mitochondrial Dysfunction.

Okui Takehito T Iwashita Masaya M Rogers Maximillian A MA Halu Arda A Atkins Samantha K SK Kuraoka Shiori S Abdelhamid Ilyes I Higashi Hideyuki H Ramsaroop Ashisha A Aikawa Masanori M Singh Sasha A SA Aikawa Elena E

Arteriosclerosis, thrombosis, and vascular biology 20201224 2

<h4>Objective</h4>Vascular calcification is a critical pathology associated with increased cardiovascular event risk, but there are no Food and Drug Administration-approved anticalcific therapies. We hypothesized and validated that an unbiased screening approach would identify novel mediators of human vascular calcification. Approach and Results: We performed an unbiased quantitative proteomics and pathway network analysis that identified increased CROT (carnitine O-octanoyltransferase) in calci ...[more]

PMID: 33356393

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