INTRODUCTION: The apolipoprotein E ( METHODS: We classified the RESULTS: The baseline serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly lower in carriers of CONCLUSION Polymorphism in the
Apolipoproteins E/genetics* ; Atherosclerosis/genetics* ; Cardiovascular Diseases ; Genotype ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use* ; Lipids

OBJECTIVE: To assess the influence of apolipoprotein E (ApoE) gene polymorphisms on the therapeutic effect of lipid-lowering statins in patients with ischemic cerebral infarction. METHODS: One hundred and six patients with ischemic cerebral infarction who orally took lipid-lowering statins for 3 months were enrolled. Changes in serum triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) before and after the drug administration were analyzed. ApoE gene polymorphisms were detected by real-time fluorescent quantitative PCR, and genotypes of ApoE gene in patients with different effects were compared. RESULTS: The detection rates for E2/E2, E2/E3, E3/E3, E2/E4 and E3/E4 genotypes were 0.94%, 11.32%, 63.21%, 1.89% and 22.64%, respectively. And the detection rates for E2, E3 and E4 alleles were 7.55%, 80.19% and 12.26%, respectively. Biochemical phenotypes included E2 type (13 cases, 12.26%), E3 type (69 cases, 65.09%) and E4 type (24 cases, 22.65%). Before administration, TG and TC of E2 type were the highest (P<0.05), but no significant difference was detected in HDL-C and LDL-C among the three phenotypes (P>0.05).Following the drug administration, TG, TC and LDL-C were decreased, while HDL-C was increased. HDL-C of E2 type was the highest, TC and LDL-C of E4 type were the highest (P<0.05). The E3/E3 ratio in low-efficiency group at admission was lower than that in the high-efficiency group, while the E3/E4 ratio was higher than that in the high-efficiency group (P<0.05). The proportion of E3 allele in low-efficiency group was lower than that in high-efficiency group, while the proportion of E4 allele was higher than that in high-efficiency group (P<0.05). CONCLUSION ApoE gene polymorphisms are closely correlated with the therapeutic effect of lipid-lowering statins in patients with ischemic cerebral infarction. The lipid-lowering effects are more significant in patients with E2 and E3 genotypes, but were poor in those with the E4 genotype. Personalized regimens should be applied.
Apolipoproteins E/genetics* ; Cerebral Infarction/genetics* ; Genotype ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use* ; Lipids ; Polymorphism, Genetic ; Triglycerides

Humans ; Warfarin/therapeutic use* ; Cytochrome P-450 CYP2C9/genetics* ; Anticoagulants/therapeutic use* ; Genotype ; Heart Valves ; China ; Apolipoproteins E/genetics* ; Dose-Response Relationship, Drug ; Receptors, Calcitriol/genetics*

OBJECTIVETo compare the effects of perindopril and enalapril on the development of atherosclerotic lesions in ApoE knockout mice.

METHODSApoE knockout mice were treated with perindoprilor (1.5 mg.kg(-1).d(-1), n = 20), enalapril (7.5 mg.kg(-1).d(-1), n = 20) or saline (0.2 ml saline/d, n = 20) per gavage for 20 weeks. Blood pressure and lipids were measured at the study end. Aortic root atherosclerotic plaque was then quantified and the content of collagen and the size of lipid core in the plaque assessed. Cryostat sections were used to quantify the expressions of monocyte/macrophage-2 (MOMA-2), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinases-9 (MMP-9) in the plaque by immunofluorescence method.

RESULTSBlood pressure and lipid profiles were similar among different groups. Compared with control group, the plaque areas of perindopril group and enalapril group displayed significantly decrease (25.33% and 22.86%, respectively, both P < 0.01). However, no significant different were observed in the plaque size between the different ACE inhibitors groups. Perindopril group and enalapril group also significantly decreased the size of lipid core (52.98% and 38.98%, respectively, both P < 0.01) and the expression of MOMA-2 (88.38% and 52.16%, respectively, both P < 0.01), ICAM-1 (80.87% and 49.59%, respectively, both P < 0.01), VCAM-1 (77.56% and 56.44%, respectively, both P < 0.01) and MMP-9 (86.93% and 55.56%, respectively, both P < 0.01), and increased the plaque collagen content (298.36% and 168.14%, respectively, both P < 0.01) and the effects of perindopril was superior to those of enalapril (all P < 0.05).

CONCLUSIONSACE inhibitors significantly suppressed tissue inflammation and attenuated the development of atherosclerosis in ApoE knockout mice independent of their effects on the lipid and blood pressure. Perindopril is superior to enalapril in stabilizing the plaques and has similar effect on reducing the plaque size as that of enalapril.

Angiotensin-Converting Enzyme Inhibitors ; therapeutic use ; Animals ; Apolipoproteins E ; genetics ; Atherosclerosis ; drug therapy ; pathology ; Collagen ; metabolism ; Enalapril ; therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Perindopril ; therapeutic use

OBJECTIVETo assess the effects of apolipoprotein E (APOE) polymorphism on the susceptibility of depression and the efficacy of antidepressants.

METHODSA total of 275 patients with depression, who met the diagnostic criteria of both CCMD-3 and DSM-4, were randomly assigned into venlafaxine group (n=136)and paroxetine group(n=139). Another 202 healthy subjects were enrolled as the control group. Hamilton Rating Scale for Depression (HAMD)-17 was adopted as the primary rating instrument to evaluate the severity of depression on the baseline and the end of the 1st, 2nd, 4th, 6th week after treatment, respectively. HAMD scores ≤7 was defined as remission, and the reduction of HAMD scores ≥50% was defined as response while <50% was defined as invalid. PCR-restriction fragment length polymorphisms (PCR-RFLP) was applied to detect the genetic polymorphism of the APOE in the case groups and control group.

RESULTSIn the venlafaxine group, the remission rate was 52.9%(n=72), the response rate was 26.5%(n=36), and the invalid rate was 20.6%(n=28), whereas the corresponding data in the paroxetine group wee 42.4%(n=59), 31.7%(n=44), and 25.9% (n=36), respectively. There were no significant differences in the efficacy between the two groups(p>0.05). In the venlafaxine group, there were no significant differences in the genotypes and the allele distribution frequency of APOEΕ2/Ε3/Ε4 between the remitters, nonremitters, and healthy controls at the end of the 6th week(p>0.05), but there was significant differences in the allele distribution frequency between the nonremitters and healthy controls(p=0.02). In paroxetine group, there were no significant differences in the genotypes and the allele distribution frequency of APOEΕ2/Ε3/Ε4 among the remitters, nonremitters and healthy controls at the end of the 6th week(p>0.05), but there were significant differences in the allele distribution frequency between the nonremitters and healthy controls (p=0.04); in addition, there were also significant differences in Ε2/Ε3 and Ε4 allele between the two groups (p=0.014).

CONCLUSIONSThe APOE gene may not play a major role in the pathogenesis of major depression. The efficacy of venlafaxine is same as paroxetine after treatment for six weeks. The APOE (Ε2+Ε3) allele may be an indicator of the bad efficacy of paroxetine treatment.

Adolescent ; Adult ; Aged ; Antidepressive Agents ; therapeutic use ; Apolipoproteins E ; genetics ; Cyclohexanols ; therapeutic use ; Depression ; drug therapy ; genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Paroxetine ; therapeutic use ; Polymorphism, Genetic ; Treatment Outcome ; Venlafaxine Hydrochloride ; Young Adult

OBJECTIVETo study the effect of atorfastatin on the cognitive function of patients with vascular cognitive impairment (VCI) and different apolipoprotein E genotypes.

METHODSThe ApoE polymorphism was genotyped by PCR sequencing and the patients were divided into Eepsilon4 carrier (epsilon4+) group (n=24) and epsilon4- group (n=51). All the patients were given 20 mg oral atorfastatin every evening. The indices of TC, TG, HDL-C, LDL-C, as well as the scores of MMSE and clock-drawing test were compared between the two groups before and 24 weeks after the treatment.

RESULTSCompared with those without epsilon4 allele, epsilon4+ patients had obviously increased plasma LDL level and lowered scores of MMSE. Plasma TC, TG and LDL-C were decreased significantly in the two groups after the treatment, and the improvement of TC was greater in patients without epsilon4 allele. The scores of MMSE increased significantly in patients with epsilon4 allele. The improvement in the scores of MMSE and clock-drawing test was greater in epsilon4+ group than in epsilon4- group.

CONCLUSIONAtorfastatin may improve the cognitive function in patients with VCI carrying epsilon4 allele, the effect of which may not be related to lowed blood lipids.

Aged ; Apolipoproteins E ; genetics ; Atorvastatin Calcium ; Cognition Disorders ; drug therapy ; genetics ; Dementia, Vascular ; drug therapy ; genetics ; Female ; Genotype ; Heptanoic Acids ; therapeutic use ; Humans ; Male ; Middle Aged ; Neuroprotective Agents ; therapeutic use ; Pyrroles ; therapeutic use

Adolescent ; Apolipoproteins E ; blood ; Humans ; Hyperlipoproteinemias ; complications ; Hypolipidemic Agents ; therapeutic use ; Kidney Diseases ; blood ; drug therapy ; pathology ; Kidney Glomerulus ; blood supply ; pathology ; Male ; Thrombosis ; pathology

OBJECTIVETo observe monocyte (Mo) development in wild type C57BL/6 mice and apoE gene knockout (apoE(-/-)) mice, and to evaluate the immuno-regulatory effect of Huanglian Jiedu Decoction (HJD) on peripheral Mo development in apoE(-/-) mice.

METHODSFour, 8, 12, and 16 weeks old female C57BL/6 mice were set up as control groups of different ages, while 4, 8, 12, and 16 weeks old female apoE(-/-) mice were set up as hyperlipidemia groups of different ages. Four-week old female C57BL/6 mice were recruited as a blank group. Four-week old female apoE(-/-) mice were randomly divided into the control group, the Western medicine group, and the Chinese medicine group by paired comparison, 5 in each group. Equivalent clinical dose was administered to mice according to body weight. Mice in the Western medicine group were administered with Atrovastatin at the daily dose of 10 mg/kg by gastrogavage, while those in the Chinese medicine group were administered with HJD at the daily dose of 5 g/kg by gastrogavage. Body weight was detected each week. After 4 weeks blood lipids levels (such as TG, TC, LDL-C, and HDL-C), and the proportions of Mo and Ly6c(hi) were detected.

RESULTSCompared with 4-week-old homogenic mice, the proportion of Mo decreased in 16-week-old C57BL/6 mice (P < 0.05). Levels of TC and TG, and the proportion of Ly6c(hi) subtype increased, but the proportion of Mo de- creased in 8-week-old apoE(-/-) mice (P <0. 05). Levels of TC, TG, and LDL-C increased in 12-week-old apoE(-/-) mice (P < 0.05). Levels of TC, TG, LDL-C, and HDL-C increased in 16-week-old apoE(-/-) mice (P < 0.05, P < 0.01). Compared with 8-week-old homogenic mice, the proportion of Mo decreased in 16-week-old C57BL/6 mice (P < 0.05); levels of TC and LDL-C increased in 12-week-old apoE(-/-) mice (P < 0.05); levels of TC and HDL-C increased in 16-week-old apoE(-/-) mice (P < 0.05, P < 0.01). Compared with C57BL/6 mice of the same age, TC and TG increased, HDL-C decreased (P < 0.01) in 4-and 8-week-old apoE(-/-) mice (P < 0.01); levels of TC, TG, LDL-C increased, and HDL-C level decreased in 12- and 16-week-old apoE(-/-) mice (P < 0.05, P < 0.01); the proportion of Mo increased in 4-week-old apoE(-/-) mice (P < 0.05); proportions of Mo and Ly6c(hi) increased in 8-week-old apoE(-/-) mice (P < 0.05). Compared with the blank control group, levels of TC, TG, and LDL-C, proportions of Mo and Ly6c(hi) increased (P < 0.01, P < 0.05), but HDL-C level decreased (P <0. 01) in the control group after intervention. Compared with the control group, body weight gained less in the Western medicine group and the Chinese medicine group (P < 0.05); the proportion of Ly6c(hi) subtype decreased in the Chinese medicine group (P < 0.05).

CONCLUSIONSIn development process blood lipids levels in apoE(-/-) mice are not only associated with age. Blood lipids levels induced growth changes in natural immune system are also correlated with age. In early stage of lipids development HJD intervention could correct this special immune disorder in apoE(-/-) mice.

Animals ; Apolipoproteins E ; genetics ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Gene Knockout Techniques ; Hyperlipidemias ; Lipids ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Monocytes ; physiology

OBJECTIVE: To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS). METHODS: Fourteen apolipoprotein E-deficient (ApoE^-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE^-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot. RESULTS: Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE^-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE^-/- mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05). CONCLUSION Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.
Mice ; Animals ; Apelin ; Tissue Plasminogen Activator/metabolism* ; Quercetin/therapeutic use* ; AMP-Activated Protein Kinases/metabolism* ; Sirtuin 1/metabolism* ; Signal Transduction/physiology* ; Atherosclerosis/metabolism* ; Apolipoproteins E

Objective: To explore the possible anti-atherosclerotic mechanisms of glucose co-transporter-2 inhibitor canagliflozin. Methods: ApoE^-/-mice fed on Western diet were randomly assigned into the model group (n=10) and the canagliflozin group (n=10). C57BL/6J mice fed on normal diet were chosen as the control group (n=10). Mice in the canagliflozin group were gavaged with canagliflozin for 14 weeks. The presence and severity of atherosclerosis were evaluated with HE and oil red O stainings in aortic root section slices. PCR assay was performed to determine the mRNA expression levels of nitric oxide synthase. Hepatic transcriptome analysis and hepatic amino acid detection were conducted using RNA-seq and targeted LC-MS, respectively. Results: HE staining and oil red O staining of the aortic root showed that AS models were successfully established in ApoE^-/-mice fed on Western diet for 14 weeks. Canagliflozin alleviated the severity of atherosclerosis in pathology. Hepatic transcriptome analysis indicated that canagliflozin impacted on amino acid metabolism, especially arginine synthesis in ApoE^-/-mice. Targeted metabolomics analysis of amino acids showed that canagliflozin reduced hepatic levels of L-serine, L-aspartic acid, tyrosine, L-hydroxyproline, and L-citrulline, but raised the hepatic level of L-arginine. Compared to the model group, the canagliflozin group exhibited higher serum arginine and nitric oxide levels as well as elevated nitric oxide mRNA expression in aortic tissues (P<0.05). Conclusion: Canagliflozin regulated the amino acid metabolism, reduced the levels of glucogenic amino acids,and promoted the synthesis of arginine in atherosclerotic mice.
Mice ; Animals ; Canagliflozin/therapeutic use* ; Nitric Oxide ; Mice, Knockout ; Mice, Inbred C57BL ; Atherosclerosis/drug therapy* ; Arginine ; Amino Acids ; Apolipoproteins E ; RNA, Messenger ; Plaque, Atherosclerotic ; Azo Compounds