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Kenneth K Wu

Publications and source records attributed to Kenneth K Wu.

At least 19 recordsLinked to original sources
PubMed2006

Diabetic atherosclerosis mouse models.

Coronary heart disease (CHD) due to atherosclerosis is the leading cause of death in the USA, and accelerated CHD has emerged as a leading cause of morbidity and mortality in diabetic patients in the USA and worldwide. This has highlighted the importance and urgency of studying the mechanism of diabetic atherosclerosis and exploring therapeutic options. Due to its unique advantages over other animal models, the mouse is the most used model for studying the mechanism of diabetes-accelerated atherosclerosis and exploring effective therapeutic approaches. In the past decade, several diabetic atherosclerosis mouse models have been established. Currently, however, there is no ideal animal model for diabetic atherosclerosis. To determine the characteristics of the models that more closely resemble human diabetic atherosclerosis disease, this review focuses on the common diabetic atherosclerosis mouse models with respect to the following issues: (1) whether the mice retain diabetic condition; (2) whether the diabetes accelerates atherosclerosis or increases atherogenic inflammation; (3) whether these factors respond to medical interventions. The discussion is aimed at identifying different diabetic mouse models and their features, in order to heighten awareness of the appropriate models that may provide useful tools for studying the mechanism of diabetes-accelerated atherosclerosis and evaluating therapeutic options.

Aldehyde Reductase↗
PubMed2006

Essential role of C-Rel in nitric-oxide synthase-2 transcriptional activation: time-dependent control by salicylate.

To determine the role of C-Rel in nitric-oxide synthase-2 (NOS-2) transcriptional activation, we evaluated the effect of lipopolysaccharide and interferon-gamma (LPS/IFNgamma) on C-Rel DNA binding in RAW 264.7. LPS/IFNgamma-stimulated C-Rel binding peaked at 4 to 8 h and declined at 24 h. Transfection of cells with a C-Rel small interfering RNA abrogated C-Rel binding at all time points. LPS/IFNgamma produced superoxide at 4 h, which subsided at 8 h. C-Rel binding and NOS-2 expression were abrogated by superoxide dismutase or apocynin at 4 h, suggesting a key role that superoxide plays in mediating C-Rel binding and NOS-2 transactivation only at 4 h. We have reported previously that salicylate at 10(-5) M inhibited LPS/IFNgamma-induced CCAAT/enhancer binding protein beta (C/EBPbeta) binding at 4 h but not at 8 or 24 h. A single dose of salicylate did not inhibit C-Rel binding at any time point. The addition of a second dose of salicylate 4 h before an indicated endpoint suppressed C-Rel but not C/EBPbeta or interferon-gamma-regulated factor-1 binding at 8 and 24 h. A single dose of salicylate added with LPS/IFNgamma inhibited NOS-2 expression only at 4 h. However, salicylate supplement inhibited NOS-2 promoter activities and mRNA and protein levels throughout 24 h. Signal profiling with a panel of inhibitors revealed time-dependent switch of signaling pathways. These results demonstrate temporal regulation of transactivator binding by LPS/IFNgamma via evolving signaling pathways. We propose that salicylate inhibits C/EBPbeta binding at 4 h and C-Rel binding at 8 and 24 h by targeting related kinases.

Animals↗
PubMed2006

An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study.

BACKGROUND: There has been interest in recent years in whether additional, and in particular novel, risk factors or blood markers, such as C-reactive protein, can enhance existing coronary heart disease (CHD) prediction models. METHODS: Using a series of case-cohort studies, the prospective Atherosclerosis Risk in Communities (ARIC) Study assessed the association of 19 novel risk markers with incident CHD in 15,792 adults followed up since 1987-1989. Novel markers included measures of inflammation, endothelial function, fibrin formation, fibrinolysis, B vitamins, and antibodies to infectious agents. Change in the area under the receiver operating characteristic curve (AUC) was used to assess the additional contribution of novel risk markers to CHD prediction beyond that of traditional risk factors. RESULTS: The basic risk factor model, which included traditional risk factors (age, race, sex, total and high-density lipoprotein cholesterol levels, systolic blood pressure, antihypertensive medication use, smoking status, and diabetes), predicted CHD well, as evidenced by an AUC of approximately 0.8. The C-reactive protein level did not add significantly to the AUC (increase in AUC of 0.003), and neither did most other novel risk factors. Of the 19 markers studied, lipoprotein-associated phospholipase A(2), vitamin B(6), interleukin 6, and soluble thrombomodulin added the most to the AUC (range, 0.006-0.011). CONCLUSIONS: Our findings suggest that routine measurement of these novel markers is not warranted for risk assessment. On the other hand, our findings reinforce the utility of major, modifiable risk factor assessment to identify individuals at risk for CHD for preventive action.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

Protection of endothelial survival by peroxisome proliferator-activated receptor-delta mediated 14-3-3 upregulation.

OBJECTIVE: To determine the role of prostacyclin (PGI2) in protecting endothelial cells (ECs) from apoptosis and elucidate the protective mechanism. METHODS AND RESULTS: To evaluate the effect of PGI2 on EC survival, we treated ECs with Ad-COX1/PGIS (Ad-COPI), which augmented selectively PGI2 production or carbaprostacyclin (cPGI2) followed by H2O2 for 4 hours. Ad-COPI inhibited annexin V-positive cells and blocked caspase 3 activation. cPGI2 inhibited apoptosis in a concentration-dependent manner. L-165041 had a similar effect, suggesting the involvement of peroxisome proliferator-activated receptor-delta (PPARdelta). ECs expressed functional PPARdelta. PPARdelta overexpression enhanced whereas PPARdelta knockdown by small interfering RNA abrogated the antiapoptotic action of cPGI2 and L-165041. Our results show for the first time that PGI2 stimulated 14-3-3alpha expression via PPARdelta activation. cPGI2 and L-165041 induced binding oaf PPARdelta to PPAR response elements located between -1426 and -1477 of 14-3-3alpha promoter region, thereby activating 14-3-3alpha promoter activity and protein expression. Upregulation of 14-3-3alpha proteins resulted in an increase in Bad binding to 14-3-3alpha and a reduction in Bad translocation to mitochondria. CONCLUSIONS: PGI2 protects ECs from H2O2-induced apoptosis by inducing PPARdelta binding to 14-3-3alpha promoter, thereby upregulating 14-3-3alpha protein expression. Elevated 14-3-3alpha augments Bad sequestration and prevents Bad-triggered apoptosis.

14-3-3 Proteins↗
PubMed2006

Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans.

Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D2 in plasma and could be blocked by pretreatment with aspirin. Two PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous vasodilation, and DP2-/- mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2- and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1+/+, DP1+/-, and DP1-/- mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP-/- mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans.

Adolescent↗
PubMed2006

Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding.

Melatonin has been shown to be produced by nonpineal cells and possess anti-inflammatory actions in animal models. In the present study, we tested the hypothesis that melatonin suppresses the expression of proinflammatory genes such as cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (INOS) by a common transcriptional mechanism. Melatonin but not tryptophan or serotonin inhibited lipopolysaccharide (LPS)-induced COX-2 and iNOS protein levels and promoter activities in RAW 264.7 cells in a time- and concentration-dependent manner. LPS or LPS plus interferon-gamma (IFNgamma) increased binding of all 5 isoforms of NF-kappaB to COX-2 and iNOS promoters. Melatonin selectively inhibited p52 binding without affecting p100 expression, p52 generation from p100, or p52 nuclear translocation. p52 acetylation was enhanced by LPS, which was abrogated by melatonin. Melatonin inhibited p300 histone acetyltransferase (HAT) activity and abrogated p300-augmented COX-2 and iNOS expression. HAT inhibitors suppressed LPS-induced p52 binding and acetylation to an extent similar to melatonin, and melatonin did not potentiate the effect of HAT inhibitors. These results suggest that melatonin inhibits COX-2 and iNOS transcriptional activation by inhibiting p300 HAT activity, thereby suppressing p52 acetylation, binding, and transactivation.

Acetylation↗
PubMed2006

Hypercoagulable states and strokes.

Several hematologic disorders and hemostatic defects increase risk of ischemic stroke. A common feature of these disorders is the creation of a prothrombotic state, now commonly referred to as "hypercoagulable state." Hematologic diseases such as essential thrombocythemia, polycythemia vera, and thrombotic thrombocytopenic purpura clearly cause stroke. Effective treatment is now available for these disorders. Association of hemostatic defects with stroke risk is still at the investigational stage. Although a number of factors such as soluble thrombomodulin, fibrinogen, factor VIII, von Willebrand factor, and plasminogen activator inhibitor-1 are associated with stroke risk, their predictive values remain unknown. Furthermore, causal relationship has not been established.

Blood Coagulation↗
PubMed2006

Analysis of protein-DNA binding by streptavidin-agarose pulldown.

Binding of nuclear transactivators to sequence-specific regulatory elements on the promoter regions is of fundamental importance in gene expression and regulation. DNA-bound transactivators recruit transcription coactivators or repressors and an array of associated proteins that interact with the basal transcription factors, thereby activating the transcription machinery. Analysis of the large complex of proteins that bind to DNA is an important step in elucidating the mechanisms by which gene expressions are regulated. Commonly used techniques to determine DNA-protein binding such as the electrophoretic mobility shift assay (EMSA) have limited value for analyzing simultaneously a large number of proteins in the complex. We describe here a streptavidin-agarose pulldown assay that is capable of analyzing quantitatively binding of an array of proteins to DNA probes. The assay is easy to perform and does not require radiolabeled probes. It involves incubation of nuclear extract proteins with 5'biotinylated double-stranded DNA probes and streptavidin-agarose beads. The complex is pulled down, and proteins in the complex are dissociated and analyzed by Western blotting. This method has been shown to be useful in determining the regulation of binding of transactivators, p300/CBP, and associated proteins to the cyclooxygenase-2 (COX-2) promoter.

Animals↗
PubMed2006

Transcription-based COX-2 inhibition: a therapeutic strategy.

Potent selective cyclooxygenase-2 (COX-2) inhibitors are effective in controlling inflammatory disorders but are associated with cardiovascular complications. Their clinical use has been severely limited. We propose that transcription-based inhibition of COX-2 expression represents a therapeutic strategy that may circumvent the undesired complications of COX-2 inhibitors. Reported data from several laboratories including ours have identified C/EBPbeta as a key transactivator mediating COX-2 transcriptional activation induced by diverse pro-inflammatory mediators. Results from our recent work show that sodium salicylate at pharmacological concentrations inhibits C/EBPbeta binding to COX-2 promoter by direct inhibition of p90 ribosomal S6 kinase (RSK). RSK phosphorylates C/EBPbeta and stimulates its binding to enhancer elements. We propose that RSK1/2 is a potential target for screening drugs with novel anti-inflammatory and anti-neoplastic therapeutic potentials.

Animals↗
PubMed2005

15d-prostaglandin J2 protects brain from ischemia-reperfusion injury.

OBJECTIVE: Brain expresses abundant lipocalin-type prostaglandin (PG) D2 (PGD2) synthase but the role of PGD2 and its metabolite, 15-deoxy-Delta(12,14) PGJ2 (15d-PGJ2) in brain protection is unclear. The aim of this study is to assess the effect of 15d-PGJ2 on neuroprotection. METHODS AND RESULTS: Adenoviral transfer of cyclooxygenase-1 (Adv-COX-1) was used to amplify the production of 15d-PGJ2 in ischemic cortex in a rat focal infarction model. Cortical 15d-PGJ2 in Adv-COX-1-treated rats was increased by 3-fold over control, which was correlated with reduced infarct volume and activated caspase 3, and increased peroxisome proliferator activated receptor-gamma (PPARgamma) and heme oxygenase-1 (HO-1). Intraventricular infusion of 15d-PGJ2 resulted in reduction of infarct volume, which was abrogated by a PPARgamma inhibitor. Rosiglitazone infusion had a similar effect. 15d-PGJ2 and rosiglitazone at low concentrations suppressed H2O2-induced rat or human neuronal apoptosis and necrosis and induced PPARgamma and HO-1 expression. The anti-apoptotic effect was abrogated by PPARgamma inhibition. CONCLUSIONS: 15d-PGJ2 suppressed ischemic brain infarction and neuronal apoptosis and necrosis in a PPARgamma dependent manner. 15d-PGJ2 may play a role in controlling acute brain damage induced by ischemia-reperfusion.

Adenoviridae↗
PubMed2005

Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Measurement of inflammatory markers has been reported to identify individuals at increased risk for ischemic stroke. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a proinflammatory enzyme secreted by macrophages. We assessed Lp-PLA2 and C-reactive protein (CRP) levels along with traditional risk factors to examine their relation to ischemic stroke. METHODS: A proportional hazards model was used in a prospective case-cohort study of 12,762 apparently healthy middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study who were observed for about 6 years. RESULTS: Mean Lp-PLA2 and CRP levels adjusted for sex, race, and age were higher in the 194 stroke cases than the 766 noncases, whereas low-density lipoprotein cholesterol (LDL-C) level was not significantly different. Both Lp-PLA2 and CRP levels were associated with ischemic stroke after adjustment for age, sex, and race: hazard ratios were 2.23 for the highest vs the lowest tertile of Lp-PLA2 and 2.70 for CRP level higher than 3 vs lower than 1 mg/L. In a model that included smoking, systolic hypertension, lipid levels, and diabetes, Lp-PLA2 and CRP levels in the highest category were associated with hazard ratios of 1.91 (95% confidence interval, 1.15-3.18; P = .01) and 1.87 (95% confidence interval, 1.13-3.10; P = .02), respectively. Individuals with high levels of both CRP and Lp-PLA2 were at the highest risk after adjusting for traditional risk factors compared with individuals with low levels of both, whereas others were at intermediate risk. CONCLUSION: Levels of Lp-PLA2 and CRP may be complementary beyond traditional risk factors in identifying middle-aged individuals at increased risk for ischemic stroke.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2005

Association of 22q11 deletion with isolated congenital heart disease in three Chinese ethnic groups.

BACKGROUND: Congenital heart disease (CHD) is the most common type of heart disease among children. About 75% of DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS) includes CHD. A deletion within chromosome 22q11.2 has been identified in the majority of patients with DGS and VCFS. And 22q11.2 deletion has become one of the markers used to study CHD in these syndromes. Whether 22q11.2 deletion is associated with isolated CHD is not known and was the topic of this study. METHODS AND RESULTS: We studied the 22q11.2 deletion in three Chinese ethnic groups (Tai, Bai and Han people) with 19 sporadic, isolated CHD by genotype and haplotype analysis with D22S420 etc. 11 consecutive polymorphic microsatellite markers. Among 19 isolated CHD patients, four had Tetralogy of Fallot (TOF), five exhibited Ventricular Septal Defect (VSD), five showed Atrial Septal Defect (ASD) and 5 had Patent Ductus Arteriosus (PDA). In some isolated CHD patients, 3 Mb and 1.5 Mb deletion to chromosome 22q11.2 was found. 2 of 4 TOF (50%) and 1 of 5 VSD (20%) and 1 of 5 PDA (20%) respectively were found to have deletions at D22S944. CONCLUSIONS: 22q11.2 deletion can be detected in isolated TOF, VSD and PDA of three Chinese ethnic groups, without detectable 22q11.2 deletion in those isolated ASD patients examined thus far. Our finding may be the first to show the 22q11.2 deletion in sporadic, isolated PDA/VSD patients whose family members are without CHD. In addition, D22S420 etc. 11 consecutive polymorphic microsatellite markers are very useful for the determination of 22q11.2 deletion in isolated CHD in China.

Alleles↗
PubMed2005

P-selectin Thr715Pro polymorphism predicts P-selectin levels but not risk of incident coronary heart disease or ischemic stroke in a cohort of 14595 participants: the Atherosclerosis Risk in Communities Study.

OBJECTIVE: Inflammation, characterized by the recruitment/adhesion of circulating leukocytes by cellular adhesion molecules, plays an important role in the pathogenesis of atherosclerosis. Genetic analyses of P-selectin, a key adhesion molecule in the progression of atherosclerosis, have provided conflicting results regarding the role of variation within the P-selectin gene and risk for heart disease. No studies have examined the association of this polymorphism with stroke. Therefore, we examined the association of the P-selectin Thr715Pro polymorphism with incident coronary heart disease (CHD) and ischemic stroke among 14595 participants in the prospective cohort of the Atherosclerosis Risk in Communities (ARIC) Study. METHODS AND RESULTS: Incidences of ischemic stroke and CHD were determined through annual telephone calls and hospital and death certificate surveillance. Four hundred fifty-six validated ischemic stroke and 1533 CHD events were identified. P-selectin Pro715 allele frequency was determined in whites and African-Americans, respectively, for CHD cases (0.11, 0.02), CHD non-cases (0.11, 0.02), ischemic stroke cases (0.11, 0.02) and stroke non-cases (0.11, 0.02). The P-selectin Pro715 allele was not associated with risk of CHD or stroke in whites or African-Americans. P-selectin levels, however, were associated with the P-selectin Thr715Pro variant in whites, but not in African-Americans. CONCLUSIONS: Genotypes carrying the P-selectin Pro715 variant allele are associated with decreased P-selectin levels compared to the homozygous wild-type genotype in whites. The P-selectin Thr715Pro polymorphism is not associated with incident CHD or ischemic stroke in either whites or African-Americans.

Alleles↗
PubMed2005

Cellular and molecular biology of prostacyclin synthase.

Prostacyclin synthase (PGIS) cDNA comprises 1500 nucleotides coding for a 500 amino acid protein. It is a heme protein with spectral characteristics of cytochrome p450 (CYP). It does not possess the typical CYP mono-oxygenase activity but catalyzes the rearrangement of prostaglandin H2 to form PGI2. Analysis of its structure-function by molecular modeling and site-directed mutagenesis reveals a long substrate channel lined by hydrophobic residues. Cys-441 has been identified as the proximal axial ligand of heme. Tyr-430 is nitrated by peroxynitrite which results in reduced PGIS catalytic activity, suggesting that Tyr-430 is located close to the heme pocket. PGIS is constitutively expressed and may be upregulated by cytokines, reproductive hormones, and growth factors. It is physically colocalized with cyclooxygenases and phospholipases, and functionally coupled with these enzymes. PGIS coupling with COX-2 has been shown to play an important role in vascular protection, embryo development and implantation, and cancer growth.

Animals↗
PubMed2005

Mitochondrial localization of cyclooxygenase-2 and calcium-independent phospholipase A2 in human cancer cells: implication in apoptosis resistance.

Cyclooxygenase-2 (COX-2) is inducible by myriad stimuli. The inducible COX-2 in primary cultured human cells has been reported to localize to nuclear envelope, endoplasmic reticulum, nucleus and caveolae. As COX-2 plays an important role in tumor growth, we were interested in its subcellular location in cancer cells. We examined COX-2 localization in several cancer cell lines by confocal microscopy. A majority of COX-2 was colocalized with heat shock protein 60, a mitochondrial protein, in colon cancer (HT-29, HCT-15 and DLD-1), breast cancer (MCF7), hepatocellular cancer (HepG2) and lung cancer cells (A549) with a similar distribution pattern. By contrast, COX-2 was not localized to mitochondria in human foreskin fibroblasts or endothelial cells. Immunoblot analysis of COX-2 in mitochondrial and cytosolic fractions confirmed localization of COX-2 to mitochondria in HT-29 and DLD-1 cells but not in fibroblasts. Calcium-independent phospholipase A2 was colocalized with heat shock protein 60 to mitochondria not only in cancer cells (HT-29 and DLD-1) but also in fibroblasts. HT-29 which expressed more abundant mitochondrial COX-2 than DLD-1 was highly resistant to arachidonic acid and H2O2-induced apoptosis whereas DLD-1 was less resistant and human fibroblasts were highly susceptible. Treatment of HT-29 cells with sulindac or SC-236, a selective COX-2 inhibitor, resulted in loss of resistance to apoptosis. These results suggest that mitochondrial COX-2 in cancer cells confer resistance to apoptosis by reducing the proapoptotic arachidonic acid.

Apoptosis↗
PubMed2005

Inhibition of p90 ribosomal S6 kinase-mediated CCAAT/enhancer-binding protein beta activation and cyclooxygenase-2 expression by salicylate.

We have previously shown that salicylate at a pharmacological concentration suppresses CCAAT/enhancer-binding protein beta (C/EBPbeta) binding, thereby reducing cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase expression (Saunders, M. A., Sansores-Garcia, L., Gilroy, D. W., and Wu, K. K. (2001) J. Biol. Chem. 276, 18897-18904; Cieslik, K., Zhu, Y., and Wu, K. K. (2002) J. Biol. Chem. 277, 49304-49310). We postulated that salicylate targets a kinase that phosphorylates and activates C/EBPbeta. Here we report the identification of p90 ribosomal S6 kinase (RSK) as a target of salicylate. Salicylate inhibited RSK in vivo and blocked the activity of RSK2 purified from cells stimulated by phorbol 12-myristate 13-acetate (PMA). Mutation of the RSK-phosphorylation site (T266A) of C/EBPbeta abrogated PMA-stimulated C/EBPbeta binding activity. RSK activation was required for PMA-induced COX-2 transcriptional activation. Salicylate also inhibited Ras and extracellular signal-regulated kinase (ERK) activation induced by PMA. We conclude that salicylate inhibits C/EBPbeta-mediated COX-2 transcriptional activation by blocking RSK activity and Ras signaling pathway.

CCAAT-Enhancer-Binding Protein-beta↗
PubMed2005

Increased hypercholesterolemia and atherosclerosis in mice lacking both ApoE and leptin receptor.

Diabetes mellitus is one of the major risk factors associated with atherosclerosis and coronary heart disease but the mechanistic links between the disease and atherosclerosis are not well understood. In this study, we investigated the effect of the deletion of the long-form leptin receptor on the progression of atherosclerosis in ApoE-/- mouse. ApoE-/-;db/db double knockout mice as well as ApoE-/-;db/+ and ApoE-/- littermates were generated by crossing ApoE-/- and db/+ mice. On a regular chow diet, ApoE-/-;db/db mice at 20 weeks of age exhibited features typical of type 2 diabetes: obesity, hyperglycemia, hyperinsulinemia and dyslipidemia and had significantly accelerated atherosclerosis compared with their age-matched ApoE-/- littermates as assessed by either the percentage of the aorta bearing lesion (5.3+/-0.9% for ApoE-/-;db/db versus 1.5+/-0.5% for ApoE-/-) or by aortic lipid content ( approximately 1.5-2-fold increase in free cholesterol and approximately 3-4-fold increase in cholesteryl ester). The atherosclerosis in these ApoE-/-;db/db mice was further accelerated by feeding mice with a Western diet and markedly inhibited by fenofibrate with a 2.5- and 5.3-fold reduction of the lesion in male and female mice, respectively. The results from this study demonstrate that type 2 diabetes can accelerate atherogenesis in mice. This mouse model may provide insight into the mechanistic link between type 2 diabetes and atherosclerosis as well as serve as a valuable tool for evaluating therapeutics.

Animals↗