CROT (Carnitine O-Octanoyltransferase) Is a Novel Contributing Factor in Vascular Calcification via Promoting Fatty Acid Metabolism and Mitochondrial Dysfunction
| Autor: | Sasha A Singh, Ilyes Abdelhamid, Arda Halu, Shiori Kuraoka, Hideyuki Higashi, Samantha K. Atkins, Masanori Aikawa, Masaya Iwashita, Elena Aikawa, Maximillian A. Rogers, Takehito Okui, Ashisha Ramsaroop |
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| Rok vydání: | 2020 |
| Předmět: |
Drug
Adult Male Proteomics medicine.medical_specialty Proteome media_common.quotation_subject Myocytes Smooth Muscle Mitochondrion Muscle Smooth Vascular Article chemistry.chemical_compound Osteogenesis Internal medicine Lipidomics medicine Myocyte Animals Humans Vascular Calcification Vascular calcification Cells Cultured media_common Mice Knockout Fatty acid metabolism business.industry Cholesterol Fatty Acids Middle Aged Atherosclerosis Fibrosis Mitochondria Mice Inbred C57BL Disease Models Animal Endocrinology chemistry Carnitine Acyltransferases Receptors LDL Female Cardiology and Cardiovascular Medicine business Energy Metabolism Signal Transduction |
| Zdroj: | Arterioscler Thromb Vasc Biol |
| ISSN: | 1524-4636 |
| Popis: | Objective: 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 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 suppressed type 1 collagen secretion, and 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 LDL (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 contributing factor in vascular calcification via promoting fatty acid metabolism and mitochondrial dysfunction, as such CROT inhibition has strong potential as an antifibrocalcific therapy. |
| Databáze: | OpenAIRE |
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