Disruption of Endothelial Cell Mitochondrial Bioenergetics in Lambs with Increased Pulmonary Blood Flow
| Autor: | Sohrab Fratz, Stephen M. Black, Shruti Sharma, Monique Radman, Ruslan Rafikov, Saurabh Aggarwal, Sridevi Dasarathy, Tantiana Burns, Qing Lu, Christian Schreiber, Jeffrey R. Fineman, Johnny Wright, Sanjiv Kumar, Xutong Sun, Olga Rafikova |
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| Rok vydání: | 2013 |
| Předmět: |
Pulmonary Circulation
Physiology Clinical Biochemistry Medical Biochemistry and Metabolomics Mitochondrion Cardiovascular Biochemistry Congenital chemistry.chemical_compound Adenosine Triphosphate Enos Homeostasis Lung Heart Defects General Environmental Science Forum Original Research Communications biology Nitric Oxide Synthase Type III Pulmonary Pharmacology and Pharmaceutical Sciences Mitochondria Nitric oxide synthase Hypertension Signal Transduction medicine.drug Heart Defects Congenital Biochemistry & Molecular Biology medicine.medical_specialty Hypertension Pulmonary Nitric Oxide Arginine Nitric oxide Carnitine Internal medicine medicine Animals Molecular Biology Sheep Animal Endothelial Cells Cell Biology biology.organism_classification Disease Models Animal Endocrinology chemistry Regional Blood Flow Disease Models biology.protein General Earth and Planetary Sciences Biochemistry and Cell Biology Asymmetric dimethylarginine |
| Zdroj: | Antioxidants & redox signaling, vol 18, iss 14 |
| ISSN: | 1557-7716 1523-0864 |
| DOI: | 10.1089/ars.2012.4806 |
| Popis: | Aims: The mitochondrial dysfunction in our lamb model of congenital heart disease with increased pulmonary blood flow (PBF) (Shunt) is associated with disrupted carnitine metabolism. Our recent studies have also shown that asymmetric dimethylarginine (ADMA) levels are increased in Shunt lambs and ADMA increases the nitration of mitochondrial proteins in lamb pulmonary arterial endothelial cells (PAEC) in a nitric oxide synthase (NOS)-dependent manner. Thus, we determined whether there was a mechanistic link between endothelial nitric oxide synthase (eNOS), ADMA, and the disruption of carnitine homeostasis in PAEC. Results: Exposure of PAEC to ADMA induced the redistribution of eNOS to the mitochondria, resulting in an increase in carnitine acetyl transferase (CrAT) nitration and decreased CrAT activity. The resulting increase in acyl-carnitine levels resulted in mitochondrial dysfunction and the disruption of mitochondrial bioenergetics. Since the addition of l-arginine prevented these pathologic changes, we examined the effect of l-arginine supplementation on carnitine homeostasis, mitochondrial function, and nitric oxide (NO) signaling in Shunt lambs. We found that the treatment of Shunt lambs with l-arginine prevented the ADMA-mediated mitochondrial redistribution of eNOS, the nitration-mediated inhibition of CrAT, and maintained carnitine homeostasis. In turn, adenosine-5′-triphosphate levels and eNOS/heat shock protein 90 interactions were preserved, and this decreased NOS uncoupling and enhanced NO generation. Innovation: Our data link alterations in cellular l-arginine metabolism with the disruption of mitochondrial bioenergetics and implicate altered carnitine homeostasis as a key player in this process. Conclusion: l-arginine supplementation may be a useful therapy to prevent the mitochondrial dysfunction involved in the pulmonary vascular alterations secondary to increased PBF. Antioxid. Redox Signal. 18, 1739–1752. |
| Databáze: | OpenAIRE |
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