Endothelial-Specific Overexpression of Histone Deacetylase 2 Protects Mice against Endothelial Dysfunction and Atherosclerosis
| العنوان: | Endothelial-Specific Overexpression of Histone Deacetylase 2 Protects Mice against Endothelial Dysfunction and Atherosclerosis |
|---|---|
| المؤلفون: | Anil Bhatta, Kei Akiyoshi, Yohei Nomura, Mingming Han, Daijiro Hori, Ke Chen, Mitsunori Nakano, Deepesh Pandey |
| المصدر: | Cellular Physiology and Biochemistry, Vol 54, Iss 5, Pp 947-958 (2020) |
| بيانات النشر: | Cell Physiol Biochem Press GmbH and Co KG, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, medicine.medical_specialty, Physiology, Vasodilator Agents, Histone Deacetylase 2, Mice, Transgenic, Vasodilation, Pulse Wave Analysis, Nitric Oxide, lcsh:Physiology, Nitric oxide, lcsh:Biochemistry, Mice, 03 medical and health sciences, chemistry.chemical_compound, Apolipoproteins E, 0302 clinical medicine, Internal medicine, medicine, Animals, Humans, Oil Red O, lcsh:QD415-436, Endothelium, Endothelial dysfunction, Aorta, lcsh:QP1-981, biology, Histone deacetylase 2, Endothelial Cells, Atherosclerosis, medicine.disease, Plaque, Atherosclerotic, Lipoproteins, LDL, Mice, Inbred C57BL, Nitric oxide synthase, HEK293 Cells, 030104 developmental biology, Endocrinology, chemistry, 030220 oncology & carcinogenesis, biology.protein, Endothelium, Vascular, Sodium nitroprusside, Proprotein Convertase 9, medicine.drug, Lipoprotein |
| الوصف: | Background/aims We recently described a novel regulatory role for histone deacetylase 2 (HDAC2) in protecting endothelial cells from oxidized low-density lipoprotein (OxLDL)-induced injury. In this study, we examined the effects of endothelial-specific HDAC2 overexpression on endothelial-dependent vasorelaxation and atherogenesis in vivo. Methods Endothelial-specific HDAC2-overexpressing transgenic mice (HDAC2-Tg) were generated under control of the Tie2 promoter. An atherosclerosis model was produced by injecting HDAC2-Tg and wild-type (WT) mice with adeno-associated virus encoding a PCSK9 gain-of-function mutant under control of a liver-specific promoter and feeding them a high-fat diet for 12 weeks. Aortic stiffness in vivo was determined by measuring pulse wave velocity. Wire myography was used to measure endothelium dependent (acetylcholine) and independent (sodium nitroprusside) relaxation in isolated mice aortas. Atherosclerotic plaque burden in aortas was determined by Oil Red O staining and protein expression was determined by western blotting. Results At baseline, HDAC2-Tg mice had normal mean arterial blood pressure (MAP) and body weight, but pulse wave velocity (PWV), an inverse measure of vascular health and stiffness, was decreased, suggesting that their vessels were more compliant. Moreover, basal nitric oxide production was enhanced in the vessels of HDAC2-Tg mice as compared to that in WT controls, although no significant differences in acetylcholine (endothelial component)- or sodium nitroprusside (non-endothelial component)-mediated relaxation were observed. However, after exposure to OxLDL, aortas from HDAC2-Tg mice exhibited greater acetylcholine-induced relaxation than did those from WT mice. Thus, endothelial-specific vasodilator production was enhanced despite oxidative injury. Atherosclerosis induction in WT mice led to a significant increase in PWV, but in HDAC2-Tg mice, PWV and MAP remained unchanged. Further, aortic rings from HDAC2-Tg exhibited better endothelial-dependent vascular relaxation than did those from WT mice, but not when treated with nitric oxide synthase inhibitor L-NAME. Finally, plaque burden, determined by Oil red O staining, was significantly increased in WT, but not HDAC2-Tg mice, subjected to the atherogenic model. Deletion of endothelial HDAC2 led to impaired endothelial cell-dependent vascular relaxation and increased PWV, compared with those in littermate controls. Conclusion HDAC2 protects against endothelial dysfunction and atherogenesis induced by oxidized lipids. Hence, overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis. HDAC2-Tg mice provide an opportunity to determine the role of endothelial HDAC2 in vascular endothelial homeostasis. |
| تدمد: | 1421-9778 1015-8987 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c43aba4520a6be4db01d2ba2744e7fb1Test https://doi.org/10.33594/000000280Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c43aba4520a6be4db01d2ba2744e7fb1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14219778 10158987 |
|---|