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Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice

Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice,Zhao Ming Dong,Allison A. Brown,Denisa D. Wagner

Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice   (Citations: 94)
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Background—Adhesive interactions between leukocytes and endothelial cells are characteristic of the development of atherosclerotic lesions, but the receptors involved remain to be defined. P-selectin is an adhesion receptor expressed on activated endothelial cells or platelets and was shown to be involved in fatty streak formation in LDL receptor- deficient mice on an atherogenic diet. The main purpose of this study is to examine the role of P-selectin in the spontaneous development of advanced atherosclerosis in apoE-deficient mice. Methods and Results—We intercrossed P-selectin- deficient mice with mice lacking apoE and compared lesion development in apoE-deficient mice with P-selectin (apoE2/2 P1/1) and without P-selectin (apoE2/2 P2/2) that were fed normal mouse chow. At 4 months of age, apoE2/2 P2/2 mice had 3.5-fold smaller aortic sinus lesions than apoE2/2 P1/1 mice. These were limited to fatty streaks in the apoE2/2 P2/2 mice, whereas 70% of apoE2/2 P1/1 lesions contained smooth muscle cells. Significantly more of the aortic sinus circumference was covered by lesions in the apoE2/2 P1/1 animals. The P-selectin genotype affected macrophage recruitment, because twice as many mononuclear cells were present in the P-selectin-positive lesions. At 15 months, the lesions progressed to the fibrous plaque stage in both genotypes and spread throughout the aorta, but this process was delayed in apoE2/2 P2/2 mice. In the aortic sinus, the lesions of the apoE2/2 P2/2 mice were 2.6-fold smaller and less calcified. Conclusions—P-selectin appears to be a key adhesion receptor mediating leukocyte recruitment into lesions and promoting advanced atherosclerosis in apoE-deficient mice. (Circulation. 2000;101:2290-2295.)
Published in 2010.
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    • ... These interactions are primarily mediated by platelet-expressed P-selectin, and mice that lack P-selectin expression have significant delays in atherosclerotic lesion formation compared with control animals in two mouse models of atherosclerosis (low-density lipoprotein receptor (LDLR)-deficient or apolipoprotein E (APOE)-deficient mice...

    Joseph E. Italianoet al. Platelets and the immune continuum

    • ..., and selectin deficiency reduces leukocyte recruitment and atherosclerosis ...

    Jie Zhanget al. Regulation of Endothelial Cell Adhesion Molecule Expression by Mast Ce...

    • ...Deaths were excluded from our sudden cardiac death definition if hyperkalemia, sepsis or malignancy was listed as a contributing cause of death, or if the death occurred in hospice.Soluble P-selectin was analyzed as a log-transformed continuous variable and categorically by tertiles. Baseline characteristics were compared across tertiles using ANOVA (continuous variables) or Pearson’s χ2 test (categorical variables). We modeled the association between soluble P-selectin and time to ASCVD event, cardiovascular mortality and sudden cardiac death using Cox proportional hazards models with clustering by clinic. Survival time was defined as the time from enrollment in the study to the first ASCVD event, total cardiovascular death or sudden cardiac death with censoring at the time of non-cardiovascular death (n = 255), transplantation (n = 208) or end of follow-up (n = 106). The main model (model 1) was adjusted for demographic factors, dialysis modality (hemodialysis vs. peritoneal dialysis), comorbidity (including ICED, diabetes, prevalent CVD at dialysis initiation and congestive heart failure) and traditional cardiovascular risk factors, such as smoking and total cholesterol. Subsequent models adjust for other inflammatory markers (C-reactive protein, interleukin-6 and serum albumin; model 2) and platelet count (model 3). Interactions between soluble P-selectin tertiles and sex/race were tested in our final models. Analyses were performed using STATA Special Edition 10.0 (2008; College Station, Tex., USA) and a two-sided α of 0.05.ResultsBaseline characteristics of the study population stratified by tertiles of soluble P-selectin are shown in table 1. Mean age of the study population was 57.1 years (SD: 14.8) with similar distribution for males (mean age: 56.9; SD: 14.6) and females (mean age: 57.2; SD: 15.0). The overall study population was 30.8% black and 64.0% white, with 80.7% of the participants on hemodialysis versus 19.3% on peritoneal dialysis. CVD was common, with 42.5% of participants reporting a baseline history of CVD (35.1% among females, 49.1% among males). Increasing tertiles of soluble P-selectin were associated with younger age, white race and increased platelet count, white blood cell count, total cholesterol and C-reactive protein.1Table 1. Baseline characteristics of the study population by tertile of soluble P-selectinT01
      Within our study population, soluble P-selectin ranged between 20.0 and 364.7 ng/ml (median: 98.0). Soluble P-selectin was correlated with C-reactive protein (r = 0.09; p = 0.01), platelet count (r = 0.27; p < 0.01), white blood cell count (r = 0.25; p < 0.01) and age (r = –0.09; p = 0.01), but not with interleukin-6 (p = 0.6). Correlates of soluble P-selectin did not differ by sex (table 2). The distribution of soluble P-selectin did not differ by sex (p = 0.5), dialysis modality (p = 0.4) or diabetes (p = 0.2). Soluble P-selectin levels were lower among blacks compared with whites (p = 0.01) and higher among those with previous CVD (p = 0.01).2Table 2. Correlates of soluble P-selectin stratified by sexT02
      Follow-up time to cardiovascular mortality or censoring in the cohort ranged from 3.4 to 111.3 months (median: 38.2). Four hundred forty-one participants (200 females and 241 males) had an ASCVD event and 255 participants (116 females and 139 males) died of cardiovascular causes during follow-up. There were a total of 119 sudden cardiac deaths (52 among females and 67 among males).As the relative hazard for cardiovascular mortality with increasing levels of soluble P-selectin differed qualitatively by sex (p interaction <0.01 in model 1; p interaction = 0.01 in model 3), all models were stratified by sex. To confirm that this interaction was not driven by premenopausal women in the cohort, a sensitivity analysis was performed excluding women less than 50 years of age. Results were similar; therefore, results using all women are presented here. There was not a statistically significant interaction between race and soluble P-selectin levels for composite ASCVD events or cardiovascular mortality (p = 0.22 and p = 0.13, respectively).Table 3 presents the relative hazard of ASCVD events and cardiovascular mortality in sequentially adjusted models by sex. The relative hazard for the composite ASCVD endpoint among males in the main model (model 1) was 1.05 (95% CI: 1.01–1.09; p = 0.02) for each 0.1-log unit higher soluble P-selectin. This association attenuated after adjustment for other inflammatory markers and platelet count (HR: 1.03; 95% CI: 0.99–1.08; p = 0.2). The association with cardiovascular mortality among males was stronger with an estimated hazard ratio of 1.09 (95% CI: 1.03–1.15; p = 0.01) for each 0.1-log unit higher soluble P-selectin in the demographic and traditional cardiovascular risk factor adjusted model (model 1). This association was robust despite further adjustment for inflammatory markers (HR: 1.07; 95% CI: 1.01–1.14; p = 0.02), or additionally for platelet count (HR: 1.10; 95% CI: 1.02–1.17; p = 0.01). Among females, soluble P-selectin was not associated with either ASCVD events or cardiovascular mortality in any models.3Table 3. Relative hazards for composite ASCVD and CVD death associated with P-selectin levels, by tertile of P-selectin and by logeP-selectinT03
      Given the high burden of sudden cardiac death in dialysis patients and the observed association between soluble P-selectin and cardiovascular mortality among males, we evaluated the association between soluble P-selectin and sudden cardiac death in secondary analyses (table 4). In the demographic and traditional cardiovascular risk factor adjusted model, there was a 9% increased risk in sudden cardiac death for each 0.1-log unit higher soluble P-selectin (p = 0.05). This association was robust to further adjustment for other inflammatory markers and platelet count (HR: 1.12 for each 0.1-log unit higher soluble P-selectin; 95% CI: 1.01–1.25; p = 0.03). The highest tertile of soluble P-selectin had a greater than 3-fold increased risk of sudden cardiac death compared with the lowest tertile in the fully adjusted model (HR: 3.19; 95% CI: 1.18–8.62; p = 0.02).4Table 4. Relative hazards for sudden cardiac death associated with P-selectin levels, by tertile of P-selectin and by logeP-selectinT04
      DiscussionIn this study, we evaluated the association between soluble P-selectin levels at dialysis initiation and ASCVD. We found that baseline soluble P-selectin levels were associated with composite ASCVD, cardiovascular mortality and sudden cardiac death among males. The association with cardiovascular mortality and sudden cardiac death persisted despite adjustment for other inflammatory markers and platelet count.P-selectin is involved in the early stages of atherogenesis by recruiting leukocytes into developing atherosclerotic plaques. In mouse models of atherosclerosis, P-selectin gene knockout slowed development of atherosclerotic lesions [...

    Julia J. Sciallaet al. Soluble P-Selectin Levels Are Associated with Cardiovascular Mortality...

    • ...55 Recently, it has been shown that mice deficient in both apolipoprotein E and P-selectin have less advanced atherosclerosis compared with those deficient in apolipoprotein E alone...

    Eugenia Gkaliagkousiet al. Platelet Activation in Essential Hypertension: Implications for Antipl...

    • ...the inducible adhesion molecules, particularly VCAM-1 and P-selectin [78,79]...

    Christian H. P. Jansenet al. MRI of subclinical coronary atherosclerosis

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