Pharmacological inhibition of histone deacetylase reduces NADPH oxidase expression, oxidative stress and the progression of atherosclerotic lesions in hypercholesterolemic apolipoprotein E-deficient mice; potential implications for human atherosclerosis

D 3 dopamine receptor (D 3 R) deficient mice have renin-dependent hypertension but the hypertension is mild and is not associated with oxidative stress. In order to determine if any compensatory mechanism in the kidney is involved in the regulation of blood pressure with disruption of D 3 R, we measured the renal protein expression of dopamine receptors in D 3 R homozygous (D 3 -/-) and heterozygous (D 3 +/-) knockout mice and their wild type (D 3 +/+) littermates. D 5 dopamine receptor (D 5 R) (169±23%, reported as % of D 3 +/+, n=5/group) expression was increased but D 4 dopamine receptors protein expression (59±8%) was decreased, while no significant changes were found with D 1 and D 2 dopamine receptors. Immunocytochemistry showed a stronger renal staining of D 5 R but without a change in renal tubule cell distribution in D 3 -/- relative to D 3 +/+ mice. D 5 R abundance was also increased in D 3 +/- (205±30%, n=5/group) relative to D 3 +/+ mice, while D 1 R abundance was similar between D 3 +/- and D 3 +/+ mice. The increase in D 5 R expression was abolished while blood pressure was increased further in D 3 -/- mice fed a high salt diet. Treatment of the D 1 -like (including D 1 and D 5 receptors) antagonist, SCH23390 , increased the blood pressure to a greater extent in anesthetized D 3 -/- mice than in D 3 +/+ mice (n=4/group), suggesting that the upregulation of D 5 R may modulate the hypertension in mice caused by the disruption of D 3 R. Since dopamine inhibits the NADPH oxidase-induced production of reactive oxygen species (ROS) via the D 5 R, we also measured the protein expression of NOXs in the kidney and isoprostane in the urine. No NADPH oxidase subunit was increased in D 3 -/- and D 3 +/- mice relative to D 3 +/+ mice fed a normal or salt high salt diet, and urinary isoprostane excretion was also similar in D 3 -/- and D 3 +/+ mice. Our findings suggest that the upregulation of D 5 R may minimize the hypertension and prevent oxidative stress in D 3 -/- mice.

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Abstract 236: Sirt6 Heterozygosity Exacerbates Atherosclerosis in Apolipoprotein E Deficient Mice

Circulation Research ◽

10.1161/res.115.suppl_1.236 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

De-Pei Liu ◽

Zhu-Qin Zhang ◽

Si-Cong Ren ◽

Zuo-Zhi Li ◽

Ying Tan ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Apolipoprotein E ◽

Histone Deacetylase ◽

Epigenetic Modification ◽

Atherosclerotic Plaques ◽

Nkg2d Ligand ◽

Class Iii ◽

Ligand Expression ◽

Atherosclerosis Development ◽

Deficient Mice

Sirt6 is a member of the class III histone deacetylase family and is reported to promote longevity. Whether Sirt6 is involved in atherosclerosis, one aging associated disease and the major cause of cardiovascular diseases, is unknown. We investigated effects of Sirt6 on atherosclerosis development. We found that in human atherosclerotic plaques, Sirt6 expression was decreased. Sirt6+/-ApoE-/- mice exhibited increased atherosclerosis development and decreased plaque stability than ApoE-/- mice. We found that Sirt6 downregulation showed increased expression of NKG2D ligands (H60b in mice and MICA/B in human). Sirt6 bound to promoters of these genes and regulated the H3K9 acetylation levels. Thus, atherosclerosis development was promoted by Sirt6 heterozygosity and epigenetic modification of NKG2D ligand expression is involved in this process.

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Chronic iron overload intensifies atherosclerosis in apolipoprotein E deficient mice: Role of oxidative stress and endothelial dysfunction

Life Sciences ◽

10.1016/j.lfs.2019.116702 ◽

2019 ◽

Vol 233 ◽

pp. 116702 ◽

Cited By ~ 12

Author(s):

Vinícius Bermond Marques ◽

Marcos André Soares Leal ◽

Jandinay Gonzaga Alexandre Mageski ◽

Helbert Gabriel Fidelis ◽

Breno Valentim Nogueira ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Iron Overload ◽

Apolipoprotein E ◽

Deficient Mice

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Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/3201062 ◽

2019 ◽

Vol 2019 ◽

pp. 1-17 ◽

Cited By ~ 6

Author(s):

Mihaela-Loredana Vlad ◽

Simona-Adriana Manea ◽

Alexandra-Gela Lazar ◽

Monica Raicu ◽

Horia Muresian ◽

...

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Histone Acetyltransferase ◽

Gene Promoter ◽

Epigenetic Mechanism ◽

Human Macrophages ◽

Inflammatory Conditions ◽

Gene And Protein Expression ◽

Human Atherosclerosis ◽

Nadph Oxidase 5

Histone acetylation plays a major role in epigenetic regulation of gene expression. Monocyte-derived macrophages express functional NADPH oxidase 5 (Nox5) that contributes to oxidative stress in atherogenesis. The mechanisms of Nox5 regulation are not entirely elucidated. The aim of this study was to investigate the expression pattern of key histone acetyltransferase subtypes (p300, HAT1) in human atherosclerosis and to determine their role in mediating the upregulation of Nox5 in macrophages under inflammatory conditions. Human nonatherosclerotic and atherosclerotic tissue samples were collected in order to determine the expression of p300 and HAT1 isoforms, H3K27ac, and Nox5. In vitro determinations were done on human macrophages exposed to lipopolysaccharide in the absence or presence of histone acetyltransferase inhibitors. Western blot, immunohistochemistry, immunofluorescence, real-time PCR, transfection, and chromatin immunoprecipitation assay were employed. The protein levels of p300 and HAT1 isoforms, H3K27ac, and Nox5 were found significantly elevated in human atherosclerotic specimens. Immunohistochemistry/immunofluorescence staining revealed that p300, HAT1, H3K27ac, H3K9ac, and Nox5 proteins were colocalized in the area of CD45+/CD68+ immune cells and lipid-rich deposits within human atherosclerotic plaques. Lipopolysaccharide induced the levels of HAT1, H3K27ac, H3K9ac, and Nox5 and the recruitment of p300 and HAT1 at the sites of active transcription within Nox5 gene promoter in cultured human macrophages. Pharmacological inhibition of histone acetyltransferase significantly reduced the Nox5 gene and protein expression in lipopolysaccharide-challenged macrophages. The overexpression of p300 or HAT1 enhanced the Nox5 gene promoter activity. The histone acetyltransferase system is altered in human atherosclerosis. Under inflammatory conditions, HAT subtypes control Nox5 overexpression in cultured human macrophages. The data suggest the existence of a new epigenetic mechanism underlying oxidative stress in atherosclerosis.

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