Upregulation of Angiotensin II Type 2 Receptor (agtr2) Attenuates Atherosclerotic Lesion Formation and Enhances Apoptosis in the LDL Receptor Knockout Mice Fed High Cholesterol Diet

2009 ◽  
pp. 151-163
Author(s):  
Jawahar L. Mehta ◽  
Magomed Khaidakov ◽  
Changping Hu ◽  
Giusto Spagnolli ◽  
Dayuan Li
Keyword(s):  
Angiotensin Ii ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Ldl Receptor Knockout Mice ◽  
Atherosclerotic Lesion Formation

Heme Oxygenase-1 Inhibits Atherosclerotic Lesion Formation in LDL-Receptor Knockout Mice

2001 ◽  
Vol 88 (5) ◽  
pp. 506-512 ◽  
Author(s):  
Kazunobu Ishikawa ◽  
Daisuke Sugawara ◽  
Xu-ping Wang ◽  
Kazunori Suzuki ◽  
Hiroyuki Itabe ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Heme Oxygenase 1 ◽  
Lesion Formation ◽  
Ldl Receptor Knockout Mice ◽  
Atherosclerotic Lesion Formation

Administration of Low-Dose Cyclophosphamide Reduces Progression of Atherosclerosis in Mice by Controlling the Cellular Microenvironment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4452-4452
Author(s):  
Yayoi Sato ◽  
Yuichi Ohki ◽  
Haruyo Akiyama ◽  
Hiroyuki Daida ◽  
Beate Heissig ◽  
...  
Keyword(s):  
Risk Factors ◽  
Drinking Water ◽  
Atherosclerotic Lesion ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Lesion Formation ◽  
Apoe Ko Mice ◽  
Atherosclerotic Lesion Formation ◽  
Apoe Ko

Abstract Atherosclerosis develops as a result of multiple inflammatory-fibroproliferative responses and is the primary cause of heart disease and stroke in Western countries. Circulating BM-derived progenitor cells (CFU-Cs or EPCs) can regenerate injured vasculature by accelerating reendothelialization and limiting atherosclerotic lesion formation. Risk factors for coronary artery disease like age and diabetes reduce the number and functional activity of these cells, thus limiting the regenerative capacity. The impairment of stem/progenitor cells by risk factors may contribute to atherosclerotic disease progression. High leukocyte counts, and especially neutrophils, a marker of inflammation have been shown to be an independent risk factor and prognostic indicator of future cardiovascular outcomes. Cyclophosphamide (CY) is a synthetic antineoplastic drug, which reduces white blood cell counts (WBC), especially neutrophils, and under certain circumstances can promote hematopoietic progenitor (colony forming unit-cells, CFU-C) mobilization from the bone marrow (BM) into the circulation. We hypothesized that administration of CY limits atherosclerotic lesion formation by decreasing inflammation-associated cells, and by increasing circulating BM-derived progenitors cells. Apolipoprotein E knockout (ApoE−/ −) mice were fed a high cholesterol diet and received different doses of CY in their drinking water (37.5mg/kg/day, 18.75mg/kg/day, 9.375mg/kg/day or nothing). To control for possible effects on progenitor release a control experiment was set up in which C57/B6 received the highest CY in their drinking water (37.5mg/kg/day) or remained untreated. Peripheral blood was drawn from mice every other week. Peripheral blood mononuclear cells (PBMCs) were isolated and subjected to cultures to detect EPCs and CFU-Cs. In CY-treated mice, WBC and neutrophil counts decreased within the first 10 days after the start of the treatment as compared to non-treated controls, and stayed low over the course of the experiment (until day 70). When apoE mice receiving a high-cholesterol diet were treated with CY, the number of circulating CFU-Cs doubled, whereas no major change was found in the c57Bl/6 control group receiving only Cy. EPCs were not detectable at any time point in the CY or control apoE group. Aortic atherosclerotic tree lesion areas were approximately 50% smaller in apoE-KO mice receiving CY in their drinking water after 12 weeks on a high-cholesterol diet than control animals. Most strikingly, apoE-KO mice treated with CY showed a prolonged survival rate as compared to untreated controls. The presence of macrophage-derived foam cells is a hallmark of the atherosclerotic lesion, and an increase in their content promotes plaque instability. Immunohistochemical analysis revealed that the number of macrophages was reduced in plaques of CY-treated animals, indicating that plaques in these might be more stable. Vascular endothelial growth factor (VEGF) is expressed in atherosclerotic plaques from local macrophages and can induce metalloproteinase-9 (MMP-9). Plasma VEGF levels were lower in the CY-treatment group, coinciding with a decrease in MMP-9 plasma levels. This study demonstrates the potential clinical use of a myelosuppressive agent for the treatment of a benign, but not less “malignant” deadly disease like atherosclerosis.

scholarly journals Hematopoietic upstream stimulating factor 1 deficiency is associated with increased atherosclerosis susceptibility in LDL receptor knockout mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Menno Hoekstra ◽  
Baoyan Ren ◽  
Pirkka-Pekka Laurila ◽  
Reeni B. Hildebrand ◽  
Jarkko Soronen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Functional Expression ◽  
Upstream Stimulatory Factor ◽  
Wild Type Littermate ◽  
Brown Adipose ◽  
Total Body ◽  
Ldl Receptor Knockout Mice

AbstractTotal body upstream stimulatory factor 1 (USF1) deficiency in mice is associated with brown adipose tissue activation and a marked protection against the development of obesity and atherosclerotic lesions. Functional expression of USF1 has also been detected in monocytes and monocyte-derived macrophages. In the current study we therefore tested whether selective hematopoietic USF1 deficiency can also beneficially impact the development of atherosclerosis. For this purpose, LDL receptor knockout mice were transplanted with bone marrow from USF1 knockout mice or their wild-type littermate controls and subsequently fed a Western-type diet for 20 weeks to stimulate atherosclerotic lesion development. Strikingly, absence of USF1 function in bone marrow-derived cells was associated with exacerbated blood leukocyte (+ 100%; P < 0.01) and peritoneal leukocyte (+ 50%; P < 0.05) lipid loading and an increased atherosclerosis susceptibility (+ 31%; P < 0.05). These effects could be attributed to aggravated hyperlipidemia, i.e. higher plasma free cholesterol (+ 33%; P < 0.001) and cholesteryl esters (+ 39%; P < 0.001), and the development of hepatosteatosis. In conclusion, we have shown that hematopoietic USF1 deficiency is associated with an increased atherosclerosis susceptibility in LDL receptor knockout mice. These findings argue against a contribution of macrophage-specific USF1 deficiency to the previously described beneficial effect of total body USF1 deficiency on atherosclerosis susceptibility in mice.

Simvastatin Reduces Expression and Activity of Lipoprotein-Associated Phospholipase A2 in the Aorta of Hypercholesterolaemic Atherosclerotic Rabbits

2009 ◽  
Vol 37 (4) ◽  
pp. 1029-1037 ◽  
Author(s):  
Z Qiao ◽  
J Ren ◽  
H Chen
Keyword(s):  
Atherosclerotic Lesion ◽  
Statin Treatment ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Atherosclerotic Plaques ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Local Inflammatory Response ◽  
Plaque Instability ◽  
Significant Difference

Lipoprotein-associated phospholipase A2 (Lp-PLA2) contributes to atherosclerotic plaque instability and subsequent sudden coronary death. Statins are associated with decreased stroke risk and may improve stability of atherosclerotic plaques. The present study investigated the effect of simvastatin on expression of Lp-PLA2 levels in atherosclerotic plaques and on Lp-PLA2 activity in atherosclerotic aortas. Rabbits were a fed chow (control group) or a high-cholesterol diet (atherosclerosis group) for 12 weeks. An additional group on the high-cholesterol diet received simvastatin (5 mg/kg per day) for the last 4 weeks (simvastatin group). Lp-PLA2 activity in plasma and atherosclerotic aortas was significantly higher in the atherosclerosis group than in the control group and, consistent with this, abundant Lp-PLA2 protein was detected in plaques in the atherosclerosis group. Simvastatin significantly reduced Lp-PLA2 activity in plasma and aorta tissue, and reduced Lp-PLA2 protein level in atherosclerotic plaques. Whereas there was no significant difference in total atherosclerotic lesion area between simvastatin and atherosclerosis groups, simvastatin significantly reduced macrophage content, lipid retention and the intima/media ratio but increased the content of smooth muscle cells in atherosclerotic lesions. Thus, statin treatment markedly reduced Lp-PLA2 in both plasma and atherosclerotic plaques. This was associated with attenuation of the local inflammatory response and improved plaque stability.

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