LOX-1 Inhibition in ApoE KO Mice Using a Schizophyllan-based Antisense Oligonucleotide Therapy

Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A2) receptors is implicated in atherosclerotic, diabetes, and renal diseases. The purpose of the present study was to analyze, in isolated, perfused mouse kidneys, the participation of TP receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE-KO mice, changes in perfusion pressure were recorded. Constrictions to TP receptor ligands U 46619, arachidonic acid, PGH2, and 8-iso-PGF2α, but not those to angiotensin II, endothelin, or norepinephrine, were inhibited by the selective TP receptor antagonist Triplion (S 18886; 10 nM). Acetylcholine and prostacyclin evoked biphasic responses during methoxamine constrictions; the constrictor part was blocked by Triplion. In ApoE-KO mouse kidneys, compared with C57BL6, a specific decrease in norepinephrine response and no modification in dilator responses were observed. In diabetic ApoE-KO mouse kidneys, constrictions to U 46619 and those to 8-iso-PGF2α were significantly and selectively augmented, without modification in the expression of the TP receptor, and again without any significant change in vasodilator activity. Thus TP receptors are functional, and their activation is not involved in norepinephrine, endothelin, and angiotensin II vasoconstrictions but is implicated in the unusual vasoconstrictions to acetylcholine and prostacyclin. Increased responsiveness of TP receptors occurs in diabetic ApoE-KO mouse kidneys. Thus early changes in TP receptor-mediated vasoconstrictor activity may participate in the development of kidney disease in atherosclerosis and diabetes.

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Beneficial effects of the active principle component of Korean cabbage kimchi via increasing nitric oxide production and suppressing inflammation in the aorta of apoE knockout mice

British Journal Of Nutrition ◽

10.1017/s0007114512000633 ◽

2012 ◽

Vol 109 (1) ◽

pp. 17-24 ◽

Cited By ~ 13

Author(s):

Jeong Sook Noh ◽

Yung Hyun Choi ◽

Yeong Ok Song

Keyword(s):

Treated Group ◽

Atherogenic Diet ◽

Control Group ◽

Active Principle ◽

Enos Expression ◽

Beneficial Effects ◽

Enos Uncoupling ◽

No Bioavailability ◽

Apoe Ko Mice ◽

Apoe Ko

The present study investigated the effects of 3′-(4′-hydroxyl-3′,5′-dimethoxyphenyl)propionic acid (HDMPPA), the active principle compound of kimchi, on vascular damage in the experimental atherosclerotic animal. HDMPPA was administrated by an intraperitoneal injection of 10 mg/kg per d for 8 weeks to apoE knockout (KO) mice with an atherogenic diet containing 1 % cholesterol, and its effects were compared with vehicle-treated control mice. HDMPPA increased NO content in the aorta, accompanied by a decrease in reactive oxygen species (ROS) concentration. Furthermore, in the HDMPPA-treated group, aortic endothelial NO synthase (eNOS) expression was up-regulated compared with the control group. These results suggested that HDMPPA could maintain NO bioavailability through an increasing eNOS expression and preventing NO degradation by ROS. Furthermore, HDMPPA treatment in apoE KO mice inhibited eNOS uncoupling through an increase in vascular tetrahydrobiopterin content and a decrease in serum asymmetric dimethylarginine levels. Moreover, HDMPPA ameliorates inflammatory-related protein expression in the aorta of apoE KO mice. Therefore, the present study suggests that HDMPPA, the active compound of kimchi, a Korean functional food, may exert its vascular protective effect through the preservation of NO bioavailability and suppression of the inflammatory response.

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Dysregulation of microRNAs in spinal muscular atrophy and the response to antisense oligonucleotide therapy

Neuromuscular Disorders ◽

10.1016/j.nmd.2015.06.040 ◽

2015 ◽

Vol 25 ◽

pp. S194

Author(s):

H. Zhou ◽

F. Catapano ◽

I. Zaharieva ◽

M. Scoto ◽

J. Morgan ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Antisense Oligonucleotide ◽

Muscular Atrophy ◽

Antisense Oligonucleotide Therapy

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Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition

BioMed Research International ◽

10.1155/2016/5438589 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Zhu Zhu ◽

Bingxuan Hua ◽

Zhanxian Shang ◽

Gongsheng Yuan ◽

Lirong Xu ◽

...

Keyword(s):

Lipid Metabolism ◽

Serum Lipids ◽

Clock Genes ◽

Plaque Formation ◽

Sirtuin 1 ◽

Atheromatous Plaque ◽

Circadian Oscillation ◽

Lighting Condition ◽

Apoe Ko Mice ◽

Apoe Ko

Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice.Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice) by altering exposure to light. C57 BL/6J mice (C57 mice) and ApoE-KO mice (ApoE-KO mice) exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1) levels and rhythmicity.Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice.Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation.

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Angiotensin II is associated with activation of NF-κB-mediated genes and downregulation of PPARs

Physiological Genomics ◽

10.1152/physiolgenomics.00062.2002 ◽

2002 ◽

Vol 11 (1) ◽

pp. 21-30 ◽

Cited By ~ 197

Author(s):

Doris M. Tham ◽

Baby Martin-McNulty ◽

Yi-xin Wang ◽

Dennis W. Wilson ◽

Ronald Vergona ◽

...

Keyword(s):

Angiotensin Ii ◽

Adhesion Molecule ◽

Vascular Inflammation ◽

Aortic Aneurysms ◽

Intercellular Adhesion Molecule ◽

Ang Ii ◽

Inflammatory Genes ◽

Apoe Ko Mice ◽

Apoe Ko

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-κB (NF-κB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-κB-dependent pro-inflammatory genes in the vascular wall in an in vivo model of atherosclerosis and aneurysm formation. Six-month-old male apolipoprotein E-deficient (apoE-KO) mice were treated with ANG II (1.44 mg/kg per day for 30 days). ANG II enhanced vascular inflammation, accelerated atherosclerosis, and induced formation of abdominal aortic aneurysms. These effects of ANG II in the aorta were associated with downregulation of both PPAR-α and PPAR-γ mRNA and protein and an increase in transcription of monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-CSF), endothelial-selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) throughout the entire aorta. ANG II also activated NF-κB with increases in both p52 and p65 NF-κB subunits. In summary, these in vivo results indicate that ANG II, through activation of NF-κB-mediated pro-inflammatory genes, promotes vascular inflammation, leading to acceleration of atherosclerosis and induction of aneurysm in apoE-KO mice. Downregulation of PPAR-α and -γ by ANG II may diminish the anti-inflammatory potential of PPARs, thus contributing to enhanced vascular inflammation.

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The reciprocal relationship between adiponectin and LOX-1 in the regulation of endothelial dysfunction in ApoE knockout mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01096.2009 ◽

2010 ◽

Vol 299 (3) ◽

pp. H605-H612 ◽

Cited By ~ 28

Author(s):

Xiuping Chen ◽

Hanrui Zhang ◽

Steve McAfee ◽

Cuihua Zhang

Keyword(s):

Endothelial Cells ◽

Endothelial Dysfunction ◽

Sodium Nitroprusside ◽

Oxidized Ldl ◽

Reciprocal Relationship ◽

Reciprocal Regulation ◽

Tnf Α ◽

Ldl Uptake ◽

Apoe Ko Mice ◽

Apoe Ko

We hypothesized that the reciprocal association between adiponectin and lectin-like oxidized LDL (ox-LDL) receptor (LOX)-1 contributes to the regulation of aortic endothelial dysfunction in atherosclerosis. To test this hypothesis, endothelium-dependent (ACh) and endothelium-independent (sodium nitroprusside) vasorelaxation of isolated aortic rings from control mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE KO mice treated with either adiponectin (15 μg·day−1·mouse−1 sc for 8 days) or neutralizing antibody to LOX-1 (anti-LOX-1, 16 μg/ml, 0.1 ml/mouse ip for 7 days) were examined. Although vasorelaxation to sodium nitroprusside was not different between control and ApoE KO mice, relaxation to ACh was impaired in ApoE KO mice. Adiponectin and anti-LOX-1 restored nitric oxide-mediated endothelium-dependent vasorelaxation in ApoE KO mice. Aortic ROS formation and ox-LDL uptake were increased in ApoE KO mice. Both adiponectin and anti-LOX-1 treatment reduced ROS production and aortic ox-LDL uptake. In mouse coronary artery endothelial cells, TNF-α incubation increased endothelial LOX-1 expression. Adiponectin reduced TNF-α-induced LOX-1 expression. Consistently, in ApoE KO mice, adiponectin treatment reversed elevated LOX-1 expression in aortas. Immunofluorescence staining showed that adiponectin was mainly colocalized with endothelial cells. Although adiponectin expression was lower in ApoE KO versus control mice, anti-LOX-1 increased aortic adiponectin expression, suggesting a reciprocal regulation between adiponectin and LOX-1. Moreover, both adiponectin and anti-LOX-1 reduced NF-κB expression in ApoE KO mice. Thus, adiponectin and LOX-1 may converge on NF-κB signaling to regulate their function. In conclusion, our results indicate that the reciprocal regulation between adiponectin and LOX-1 amplifies oxidative stress and ox-LDL uptake, leading to endothelial dysfunction in atherosclerosis.

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Antisense-Oligonucleotide Therapy

New England Journal of Medicine ◽

10.1056/nejm199602013340508 ◽

1996 ◽

Vol 334 (5) ◽

pp. 316-318 ◽

Cited By ~ 81

Author(s):

Frederick K. Askari ◽

W. Michael McDonnell

Keyword(s):

Antisense Oligonucleotide ◽

Antisense Oligonucleotide Therapy

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Abstract 1444: Overexpression Of Endothelial Nitric Oxide Synthase Restores Post-natal Neovascularization In Atherosclerosis.

Circulation ◽

10.1161/circ.116.suppl_16.ii_297-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Barend Mees ◽

Ludovic Waeckel ◽

Dong You ◽

Dennie Tempel ◽

Maria Godinho ◽

...

Keyword(s):

Bone Marrow ◽

Hind Limb ◽

Fold Increase ◽

Tissue Perfusion ◽

Vessel Density ◽

Plaque Size ◽

Angiogenic Potential ◽

Apoe Ko Mice ◽

Apoe Ko

Alteration in post-ischemic neovascularization is a common complication of atherosclerotic disease. This results, at least in part, from abrogation of bone-marrow mononuclear cells (BM-MNC) pro-angiogenic potential. Overexpression of eNOS has been shown to promote vessel growth in the setting of ischemia. We hypothesized that eNOS overexpression could restore impaired neovascularization in atherosclerotic (ApoE KO) mice. Hind limb ischemia was induced in mice by right femoral artery ligation. After two weeks we evaluated tissue perfusion of the foot by Laser Doppler, vessel density in the hind limb by micro-angiography and histology, and atherosclerotic plaque size. In vitro BM-MNC cell culture assays were performed. Tissue perfusion and vessel density were 1.5-fold increased in transgenic mice overexpressing eNOS (eNOStg) as compared to wild type (WT) (P<0.001, n=10). Transplantation of 1x106 WT- or eNOStg BM-MNC in WT recipients caused a 1.5-fold increase in tissue perfusion and vessel density compared to injection of PBS (P<0.001, n=10). Next, we used ApoE KO mice and crossbreeds of eNOStg and ApoE KO mice (eNOStg*ApoE KO). Tissue perfusion and vessel density were 1.8-fold increased in eNOStg*ApoE KO mice as compared to ApoE KO mice (P<0.001, n=10). Transplantation of both WT- or eNOStg*ApoE KO BM-MNC in ApoE KO recipients caused a 1.6- to 2-fold increase in tissue perfusion and vessel density compared to PBS (P<0.01, n=10), while transplantation of ApoE KO BM-MNC had no positive effect on neovascularization. Moreover, transplantation of WT BM-MNC significantly increased plaque size, while eNOStg*ApoE KO BM-MNC had no effect on plaque size. eNOS overexpression did not affect BM-MNC apoptosis and secretion of growth factors but increased their ability to differentiate in vitro into EPC. Conclusion: eNOS overexpression in the endothelium improves post-ischemic neovascularization in both physiological as atherosclerotic settings. Furthermore, eNOS overexpression in the bone marrow restores the impaired pro-angiogenic potential of atherosclerotic BM-MNC without adverse effects on plaque size. Therefore, overexpression of eNOS could play a vital part in the development of therapeutic angiogenesis for atherosclerotic disease.

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Tetrahydrobiopterin Slows the Progression of Atherosclerosis

Pteridines ◽

10.1515/pteridines.2007.18.1.115 ◽

2007 ◽

Vol 18 (1) ◽

pp. 115-121

Author(s):

Suzuki Kunihiro ◽

Yoshiyuki Hattori ◽

Teruo Jojima ◽

Atsuko Tomizawa ◽

Toshie Okayasu ◽

...

Keyword(s):

Drinking Water ◽

Endothelial Dysfunction ◽

Nadph Oxidase ◽

Endothelial Function ◽

Oral Administration ◽

Mrna Expression ◽

Inflammatory Factors ◽

Apoe Ko Mice ◽

Progression Of Atherosclerosis ◽

Apoe Ko

Abstract We investigated whether oral tetrahydrobiopterin (BH4) treatment might slow the progression of atherosclerosis using hypercholesterolemic ApoE-knockout (KO) mice. We report that ingesting BH4 in drinking water is effective to inhibit atherogenesis in mice. Furthermore, we report that BH4 treatment improves endothelial dysfunction and attenuates increased mRNA expression of NADPH oxidase components, as well as a number of inflammatory factors, such as LOX-1 and MCP-1, in the aortas of ApoE-KO mice. Strategies such as oral administration of BH4 to ensure continuous BH4 availability may be effective in restoring NO-mediated endothelial function and limiting vascular disease and the progression of atherosclerosis.

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