The Mitochondrial Permeability Transition Pore Regulates Endothelial Bioenergetics and Angiogenesis
| Autor: | Surya Kotha, Brian J. Hawkins, Raluca Marcu, Zhongwei Zhi, Ruikang K. Wang, Ying Zheng, Wan Qin, Christopher K. Neeley |
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| Rok vydání: | 2015 |
| Předmět: |
Time Factors
Genotype Physiology Angiogenesis Neovascularization Physiologic Biology Mitochondrion Transfection Mitochondrial Membrane Transport Proteins Article Cyclophilins Mitochondrial membrane transport protein Sirtuin 1 Animals Humans Phosphorylation Cells Cultured Cell Proliferation Nicotinamide mononucleotide Mice Knockout Wound Healing Mitochondrial Permeability Transition Pore PTEN Phosphohydrolase Endothelial Cells NAD Molecular biology Mitochondria Cell biology Phenotype Mitochondrial permeability transition pore Mitochondrial matrix biology.protein Calcium RNA Interference NAD+ kinase Energy Metabolism Cardiology and Cardiovascular Medicine Proto-Oncogene Proteins c-akt Cyclophilin D Signal Transduction |
| Zdroj: | Circulation Research. 116:1336-1345 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.116.304881 |
| Popis: | Rationale: The mitochondrial permeability transition pore is a well-known initiator of cell death that is increasingly recognized as a physiological modulator of cellular metabolism. Objective: We sought to identify how the genetic deletion of a key regulatory subunit of the mitochondrial permeability transition pore, cyclophilin D (CypD), influenced endothelial metabolism and intracellular signaling. Methods and Results: In cultured primary human endothelial cells, genetic targeting of CypD using siRNA or shRNA resulted in a constitutive increase in mitochondrial matrix Ca 2+ and reduced nicotinamide adenine dinucleotide (NADH). Elevated matrix NADH, in turn, diminished the cytosolic NAD + /NADH ratio and triggered a subsequent downregulation of the NAD + -dependent deacetylase sirtuin 1 (SIRT1). Downstream of SIRT1, CypD-deficient endothelial cells exhibited reduced phosphatase and tensin homolog expression and a constitutive rise in the phosphorylation of angiogenic Akt. Similar changes in SIRT1, phosphatase and tensin homolog, and Akt were also noted in the aorta and lungs of CypD knockout mice. Functionally, CypD-deficient endothelial cells and aortic tissue from CypD knockout mice exhibited a dramatic increase in angiogenesis at baseline and when exposed to vascular endothelial growth factor. The NAD + precursor nicotinamide mononucleotide restored the cellular NAD + /NADH ratio and normalized the CypD-deficient phenotype. CypD knockout mice also presented accelerated wound healing and increased neovascularization on tissue injury as monitored by optical microangiography. Conclusions: Our study reveals the importance of the mitochondrial permeability transition pore in the regulation of endothelial mitochondrial metabolism and vascular function. The mitochondrial regulation of SIRT1 has broad implications in the epigenetic regulation of endothelial phenotype. |
| Databáze: | OpenAIRE |
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