Xiaoyun Cao (China)
The Chinese University of Hongkong School of Biomedical ScienceAuthor Of 1 Presentation
O048 - Deletion of endothelial SIRT3 enhances endothelial dysfunction, vascular inflammation, and atherosclerosis (ID 1057)
Abstract
Background and Aims
Atherosclerosis is the inflammation of vascular wall triggered by initial dysfunction of the luminal endothelial cells potentiated by dyslipidemia. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) -dependent mitochondrial deacetylase. The present study tested whether endothelial-selective Sirt3 deletion accelerates vascular inflammation and atherosclerosis and the potential effect of L-arginine to alleviate vascular inflammation associated with SIRT3 deletion.
Methods
Cdh5-Cre driven deletion of Sirt3-floxed allele was used to generate endothelium-specific Sirt3 knockout mice. Mice were injected with adeno-associated virus to overexpress PCSK9, and fed with high cholesterol diet to induce atherosclerosis. Human endothelial cell HUVECs and mouse brain microvascular endothelial cells were used for in vitro experiments.
Results
SIRT3 knockout further reduced endothelium-dependent vasodilatation impaired IL-1β in aorta, accompanied by increased production of mitochondrial superoxide. Such effect could be attenuated by treatment with NAD or L-arginine. Deletion of SIRT3 exacerbated atherosclerotic plaque formation in mice, accompanied by higher expression of E-selectin and more macrophage infiltration, with reduced vasodilatation. In human and mouse endothelial cells, SIRT3 knockdown enhanced upregulation of vascular inflammation markers including VCAM1, ICAM1, and CCL2 induced by IL1β or TNFα. Pre-treatment with NAD or L-arginine attenuated the upregulation of these adhesion molecules and chemokines. L-arginine also alleviated impaired mitochondrial respiration induced by TNFα in wild type and SIRT3 knockdown endothelial cells.
Conclusions
Our results support the role of mitochondrial SIRT3 against atherosclerotic inflammation and mitochondrial dysfunction. Further study is needed to identify the enzymes in L-arginine metabolism regulated by SIRT3 in endothelial cells (supported by RGC/GRF 14109519).
Presenter of 1 Presentation
O048 - Deletion of endothelial SIRT3 enhances endothelial dysfunction, vascular inflammation, and atherosclerosis (ID 1057)
Abstract
Background and Aims
Atherosclerosis is the inflammation of vascular wall triggered by initial dysfunction of the luminal endothelial cells potentiated by dyslipidemia. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) -dependent mitochondrial deacetylase. The present study tested whether endothelial-selective Sirt3 deletion accelerates vascular inflammation and atherosclerosis and the potential effect of L-arginine to alleviate vascular inflammation associated with SIRT3 deletion.
Methods
Cdh5-Cre driven deletion of Sirt3-floxed allele was used to generate endothelium-specific Sirt3 knockout mice. Mice were injected with adeno-associated virus to overexpress PCSK9, and fed with high cholesterol diet to induce atherosclerosis. Human endothelial cell HUVECs and mouse brain microvascular endothelial cells were used for in vitro experiments.
Results
SIRT3 knockout further reduced endothelium-dependent vasodilatation impaired IL-1β in aorta, accompanied by increased production of mitochondrial superoxide. Such effect could be attenuated by treatment with NAD or L-arginine. Deletion of SIRT3 exacerbated atherosclerotic plaque formation in mice, accompanied by higher expression of E-selectin and more macrophage infiltration, with reduced vasodilatation. In human and mouse endothelial cells, SIRT3 knockdown enhanced upregulation of vascular inflammation markers including VCAM1, ICAM1, and CCL2 induced by IL1β or TNFα. Pre-treatment with NAD or L-arginine attenuated the upregulation of these adhesion molecules and chemokines. L-arginine also alleviated impaired mitochondrial respiration induced by TNFα in wild type and SIRT3 knockdown endothelial cells.
Conclusions
Our results support the role of mitochondrial SIRT3 against atherosclerotic inflammation and mitochondrial dysfunction. Further study is needed to identify the enzymes in L-arginine metabolism regulated by SIRT3 in endothelial cells (supported by RGC/GRF 14109519).