Objective: To investigate the clinical characteristics of hereditary hypercholesterolemia in childhood. Methods: The clinical data including general conditions, clinical manifestations, laboratory tests, and genetic testing results of 4 children with hereditary hypercholesterolemia who admitted to Henan Children's Hospital from January 2020 to December 2020 were retrospectively analyzed. Results: There were 4 female children aged 5.5,1.5,6.3,3.1 years, all presented with skin xanthoxoma as the chief complaint. Plasma total cholesterol (range 11.8 to 20.9 mmol/L) and low density lipoprotein-cholesterol (range 8.2 to 13.7 mmol/L) were significantly elevated. The serum β-glutamate levels in case 1 (241.2 μmol/L) and case 2 (164.2 μmol/L) increased significantly. Genetic analysis revealed compound heterozygous variants of ABCG8 gene in case 1 and ABCG5 gene in case 2 who were diagnosed with sitosterolemia. Case 3 and 4 who all had family history of hypercholesterolemia and compound heterozygous variants of LDLR gene were diagnosed with familial hypercholesterolemia. After diet treatment, the blood lipids returned normal and the skin xanoma subsided in case 1 and 2. In case 3 and 4, the blood lipids gradually decreased after diet and rosuvastatin treatment. Conclusions: Xanthomatosis is the common clinical manifestation of sitosterolemia and familial hypercholesterolemia. Family history, blood plant sterol profile, genetic variation, and changes in blood lipids after early dietary treatment are helpful for disease identification.
Child ; Humans ; Hypercholesterolemia/genetics* ; Retrospective Studies ; Hyperlipoproteinemia Type II/genetics* ; Cholesterol, LDL

OBJECTIVETo investigate the relationship between the genetic variation of Furin gene and the hypercholesterolemia and hyper-low-density lipoprotein cholesterolemia in Kazakh general population.

METHODSBased on a cross-sectional epidemiological study in a Kazakh general population, a case-control study including 878 subjects was conducted. All the sequence variant-located promoters and exon regions of Furin gene were identified by the direct sequencing of PCR products in 48 randomly selected hypercholesterolemic individuals (24 males and 24 females). After having genotyped the representative polymorphisms in 878 subjects by TaqMan PCR, we investigated the relationship between genetic variation of Furin and hypercholesterolemia/hyper-low-density lipoprotein cholesterolemia in these subjects.

RESULTSTwelve genetic variations in Furin gene were identified by sequencing 48 hypercholesterolemic individuals and 4 common single nucleotide polymorphisms (rs6226, rs6227, rs2071410, and rs4932178)were selected as the representatives for genotyping in these subjects. The rs6226, rs6227, rs2071410, and rs4932178 polymorphisms were successfully genotyped. The distribution of the genotypes, alleles, and haplotypes of rs6226, rs6227, rs2071410, and rs4932178 polymorphisms did not differ significantly between the hypercholesterolemia group and the control groups or between the hyper-low-density lipoprotein cholesterolemia group and the control groups (all P>0.05). The cholesterol and low-density lipoprotein cholesterol levels did not differ significantly among individuals with different genotypes (all P>0.05).

CONCLUSIONThe genetic variation of Furin may not be associated with hypercholesterolemia or hyper-low-density lipoprotein cholesterolemia in Kazakh general population.

Adult ; Asian Continental Ancestry Group ; genetics ; Case-Control Studies ; Cross-Sectional Studies ; Female ; Furin ; genetics ; Humans ; Hypercholesterolemia ; ethnology ; genetics ; Male ; Middle Aged ; Polymorphism, Genetic

The past decade has seen an explosion of new information on the physiology of penile erection, and pathophysiology of erectile dysfunction (ED). Hypercholesterolemia is a chronic condition that can lead to degeneration in the vasculature bed and can result in ED if the penile vasculature is involved. Angiogenesis is the growth of new blood vessels from preexisting vasculature. Therapeutic angiogenesis seeks to harness the mechanisms of vascular growth to treat disorders of inadequate tissue perfusion, such as coronary artery disease and ED. There have been tremendous changes in the field of therapeutic angiogenesis over the past decade, and there is much promise for the future. Initial preclinical work with cytokine growth factor delivery resulted in a great deal of enthusiasm for the treatment of ischemic heart and/or peripheral vascular disease, though clinical studies have not achieved similar success. With an increased understanding of the complex mechanisms involved in angiogenesis, novel therapies which target multiple different angiogenic pathways are also being developed and tested. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Therapeutic angiogenesis is an exciting field that continues to evolve. This review will focus on the development of growth factors for hypercholesterolemic ED, the use of various growth factors for ED therapy, their routes of delivery, and the results in animal studies.
Animals ; Erectile Dysfunction ; etiology ; therapy ; Fibroblast Growth Factor 2 ; genetics ; Gene Expression ; Genetic Therapy ; Humans ; Hypercholesterolemia ; complications ; Male ; Neovascularization, Physiologic ; Nitric Oxide Synthase ; genetics ; Vascular Endothelial Growth Factors ; genetics

OBJECTIVETo detect whether the activation of nuclear factor-kappa B (NF-kappaB) in endothelial cells induced by mm-LDL can promote platelet-derived growth factor-B (PDGF-B) expression in vitro, and whether it is also present in hypercholesterolemic rats in vivo, influence of age on NF-kappaB and PDGF-B signal transduction pathway.

METHODSEstablished hypercholesterolemic rat model by feeding with a high-cholesterol ration. The activation of NF-kappaB in aortic endothelial cells was identified by immunohistochemical staining, the expression of PDGF-B mRNA and PDGF-B protein were examined using in situ hybridization and immunohistochemistry respectively.

RESULTSIn comparison with the control rats, a positive immunostaining of NF-kappaB in nuclei of aortic endothelial cells of the experimental rats was detected after a high cholesterol ration for 6 weeks. The number of endothelial cells expressing PDGF-B mRNA increased and the intensity was dependent upon the duration of high-cholesterol intake. NF-kappaB translocation (0.461 +/- 0.075 vs. 0.350 +/- 0.094, P < 0.05) and PDGF-B expression in 10-month old Wistar rats were more remarkable than that of 2-month old rats after having cholesterol for 16 weeks. Immunohistochemical staining for PDGF-B gave a similar result (0.230 +/- 0.040 vs. 0.185 +/- 0.037, P < 0.001).

CONCLUSIONSHypercholesterolemia is capable of activating nuclear translocation of NF-kappaB and promoting expression of PDGF-B in rat aortic endothelial cells in vivo, this coincided with the results obtained in ox-LDL or mm-LDL experiments on endothelial cells in vitro. This phenomenon is much more evident in 10-month old rats which indicates that age might have a close relationship with NF-kappaB - PDGF-B signal transduction pathway.

Active Transport, Cell Nucleus ; Age Factors ; Animals ; Aorta ; metabolism ; Arteriosclerosis ; etiology ; Endothelial Cells ; metabolism ; Hypercholesterolemia ; metabolism ; Immunohistochemistry ; Male ; NF-kappa B ; metabolism ; Proto-Oncogene Proteins c-sis ; analysis ; genetics ; RNA, Messenger ; analysis ; Rats ; Rats, Wistar

To study the influence of hypercholesterolemia with caveolin-1 on the plasmalemma of vascular endothelium, we used the methods of immunohistochemistry to detect the dynamic changes of caveolin-1 in cultured ECV-304 cells which were stimulated high cholesterol serum and the arterial endothelium of hypercholesterolemia rats. It is resulted that high cholesteorol level can upregulate the expression of caveolin-1 both in vitro and in vivo. In the initial stage of hypercholesterolemia model, the expression of caveolin-1 increased as the time of high cholesterol level added, but in the later period it was decreased slightly.
Animals ; Aorta ; pathology ; Caveolin 1 ; Caveolins ; biosynthesis ; genetics ; Cells, Cultured ; Cholesterol ; blood ; Endothelium, Vascular ; cytology ; metabolism ; Female ; Humans ; Hypercholesterolemia ; metabolism ; Male ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Umbilical Veins ; cytology

OBJECTIVETo establish the animal model of atherosclerotic erectile dysfunction induced by high-cholesterol diet and explore the mechanisms of atherosclerotic erectile dysfunction.

METHODSThirty male rabbits were divided into two groups randomly: normal diet (ND) group (n = 10) and high-cholesterol (HCH) group fed with 1.5% cholesterol diet (n = 20). Serum total cholesterol, plaque areas of the ascending aorta, the ratio of intima/media thickness and level of vascular cell adhesion molecule 1 (VCAM-1) mRNA expression of internal pudendal artery were determined after twelve weeks.

RESULTSAfter twelve weeks, all rabbits of the HCH group got hyperlipemia, 9 of which presented typical atherosclerosis (ATH). The rate of atherosclerosis induced by high-cholesterol diet was 52.9%. Serum total cholesterol levels of the ATH and HCH groups were higher than that of the ND group (P<0.01). The penile erection times and rate in the ATH and HCH groups decreased significantly, compared with the ND group (P<0.01). Both the ratio of intima/media thickness and the level of VCAM-1 mRNA expression of internal pudendal artery in the ATH group were higher than those in the HCH and ND groups (P<0.01).

CONCLUSIONIt is easy, prectuable and reliable to establish the animal model of atherosclerotic erectile dysfunction induced by high-cholesterol diet. And one of the main causes of atherosclerotic erectile dysfunction is hypercholesterolemia, which through VCAM-1 may induce the structural and functional modifications of the endothelium of the internal pudendal artery and make the corpus cavernosum ischemia.

Animals ; Atherosclerosis ; complications ; physiopathology ; Diet, Atherogenic ; Disease Models, Animal ; Hypercholesterolemia ; complications ; physiopathology ; Impotence, Vasculogenic ; etiology ; physiopathology ; Male ; RNA, Messenger ; biosynthesis ; Rabbits ; Random Allocation ; Vascular Cell Adhesion Molecule-1 ; biosynthesis ; genetics

OBJECTIVETo study the clinical features and ABCG5/ABCG8 gene mutations of three pedigrees of phytosterolemia presented with macrothrombocytopenia and hemolysis.

METHODSErythrocyte and platelet morphology were examined under light microscope. Plasma sterol levels were measured by high pressure/performance liquid chromatography method. All of ABCG5 and ABCG8 exons and intron-exon boundaries were directly sequenced to identify mutations, the corresponding gene mutation sites of three families members and healthy individuals were detected.

RESULTSAll the patients presented macrothrombocytopenia, hemolysis, splenomegaly and xanthomas. The blood smears showed large platelets, some as large as erythrocytes, and abnormal erythrocyte shapes, such as stomatocytes. Plasma concentrations of phytosterols, especially sitosterol were markedly elevated (30 fold) in the affected patients. Four mutations were identified in these three pedigrees, ABCG5 C20896T (R446X) and A20883G, ABCG8 del43683-43724 and del1938C-1939G/ins1938T. The latter three were novel mutations reported for the first time.

CONCLUSIONSPhytosterolemia associated with macrothrombocytopenia and hemolysis is a new subtype of this disease. Plasma phytosterols and related gene analysis should be performed when ever an unexplained macrothrombocytopenia, especially combined with haemolysis or/and stomatocytosis.

ATP Binding Cassette Transporter, Sub-Family G, Member 5 ; ATP Binding Cassette Transporter, Sub-Family G, Member 8 ; ATP-Binding Cassette Transporters ; genetics ; Adult ; Blood Platelets ; cytology ; DNA Mutational Analysis ; Erythrocytes, Abnormal ; Female ; Hemolysis ; genetics ; Humans ; Hypercholesterolemia ; genetics ; pathology ; Intestinal Diseases ; genetics ; pathology ; Lipid Metabolism, Inborn Errors ; genetics ; pathology ; Lipoproteins ; genetics ; Male ; Middle Aged ; Mutation ; Pedigree ; Phytosterols ; adverse effects ; blood ; genetics ; Platelet Count ; Thrombocytopenia ; genetics ; pathology

In our previous study, two point mutants of apolipoprotein A-I, designated V156K and A158E, revealed peculiar characteristics in their lipid-free and lipid-bound states. In order to determine the putative therapeutic potential of these mutants, several in vitro and in vivo evaluations were conducted. In the lipid-free state, V156K showed more profound antioxidant activity against LDL oxidation than did the wildtype (WT) or A158E variants in an in vitro assay. In the lipid-bound state, V156K-rHDL showed an enhanced cholesterol delivery activity to HepG2 cells in a time-dependent manner, as compared to WT-rHDL, A158E-rHDL, and R173C-rHDL. We assessed the physiological activities of the mutants in circulation, using hypercholesterolemic mice (C57BL6/J). Palmitoyloleoyl phosphatidylcholine (POPC)-rHDL preparations containing each of the apoA-I variants were injected into the mice at a dosage of 30 mg of apoA-I/kg of body weight. Forty eight hours after injection, the sera of the V156K-rHDL injected group showed the most potent antioxidant abilities in the ferric acid removal assay. The V156K-rHDL- or R173C-rHDL-injected mice showed no atherosclerotic lesions and manifested striking increases in their serum apo-E levels, as compared to the mice injected with WT-rHDL or A158E-rHDL. In conclusion, V156K-rHDL exhibited the most pronounced antioxidant activity and anti-atherosclerotic activity, both in vitro and in vivo. These results support the notion that HDL-therapy may prove beneficial due to its capacity to induce accelerated cholesterol excretion, as well as its enhanced antioxidant and anti-inflammatory effects and lesion regression effect.
Amino Acids/*genetics ; Animals ; Antioxidants/*metabolism ; Apolipoprotein A-I/*genetics ; Atherosclerosis/*pathology ; Biological Transport/drug effects ; Cell Line, Tumor ; Cholesterol/metabolism ; Copper/pharmacology ; Humans ; Hypercholesterolemia/chemically induced/*pathology ; Lipoproteins, HDL/blood ; Lipoproteins, LDL/blood ; Male ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction/drug effects ; Point Mutation/*genetics ; Recombinant Proteins/blood

OBJECTIVE: To investigate the effect of probucol and losartan on the prevention of restenosis after balloon angioplasty in hypercholesterolaemic rabbits, and to examine the expression of growth factors. METHODS: Forty male New Zealand white rabbits were randomly divided into high cholesterol diet group, probucol group, losartan group and combined drugs group. After one week of diet, all rabbits were injured on iliac arteries with balloon. Four weeks after the injury, the morphology of the iliac arteries of the rabbits were observed, and the insulin-like growth factor-I receptor (IGF-IR) and vascular endothelial growth factor (VEGF) were examined by immunohistochemical methods. RESULTS: Compared with the high cholesterol diet group, the lumen areas of the probucol group, losartan group and combined drugs group were larger (P < 0.01), the intimal areas were smaller (P < 0.05), and the expression of IGF-IR and VEGF significantly decreased (P < 0.05). There was no statistically significant difference among the three groups. CONCLUSION Probucol and losartan can prevent the restenosis of rabbits' iliac artery from balloon injury, and inhibit the expression of IGF-IR and VEGF. There is no statistical difference between combined drugs and single drug administration.
Angioplasty, Balloon ; adverse effects ; Animals ; Anticholesteremic Agents ; pharmacology ; therapeutic use ; Coronary Restenosis ; prevention & control ; Drug Therapy, Combination ; Hypercholesterolemia ; therapy ; Losartan ; pharmacology ; therapeutic use ; Male ; Probucol ; pharmacology ; therapeutic use ; Rabbits ; Random Allocation ; Receptor, IGF Type 1 ; biosynthesis ; genetics ; Vascular Endothelial Growth Factor A ; biosynthesis ; genetics

Cajanus cajan L. is a natural plant, which contains a lot of potential active components. In the present study, we identified the effects of the stilbene extract from Cajanus cajan L. (sECC) on hepatic cholesterol metabolism in diet-induced (for 4 weeks) hyperlipidemic Kunming mice. All experimental mice were divided into 5 groups: control group, high lipid model group, sECC-treated with 200 or 100 mg kg(-1), and simvastatin (Sim, 12 mg kg(-1)) treated group. The mice were fed with fat and cholesterol-enriched chow except control mice that were fed with standard diet. The effects of sECC were investigated by monitoring serum and liver lipid profile (i. e. cholesterol homeostasis) in mice. To further explore the mechanism of sECC, hepatic cholesterol 7alpha-hydroxylase (CYP7A1) and low density lipoprotein (LDL) receptor expressions in cholesterol homeostasis were analyzed by reverse transcription PCR. After 4 weeks pretreatment, the mice in the high lipid model group showed markedly higher serum and hepatic lipid contents than control group (P< 0.01). Compared with high lipid model group, the increased serum and hepatic lipid contents were markedly attenuated by sECC (200 mg kg(-1)), the serum and hepatic total cholesterol were reduced by 31.5% and 22.7% (P<0.05), respectively. The triglyceride contents of serum and liver were also lowered by 23.0% and 14.4%, respectively. At the same times, serum LDL cholesterol decreased by 53.0% (P<0.01). The mRNA expressions of hepatic CYP7A1 and LDL-receptor were significantly enhanced in the mice administered with sECC (200 mg kg(-1)), whereas those expressions were suppressed by the fat and cholesterol-enriched diet. These data indicate that sECC reduces the atherogenic properties of dietary cholesterol in mice. It is indicated that expression enhancement of hepatic LDL-receptor and cholesterol 7alpha-hydroxylase may be responsible for the hypercholesterolemic effect.
Animals ; Anticholesteremic Agents ; isolation & purification ; pharmacology ; Body Weight ; drug effects ; Cajanus ; chemistry ; Cholesterol ; blood ; metabolism ; Cholesterol 7-alpha-Hydroxylase ; biosynthesis ; genetics ; Cholesterol, LDL ; blood ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Gene Expression Regulation ; Hypercholesterolemia ; blood ; genetics ; metabolism ; pathology ; Liver ; metabolism ; pathology ; Male ; Mice ; Organ Size ; drug effects ; Plant Leaves ; chemistry ; Plants, Medicinal ; chemistry ; RNA, Messenger ; metabolism ; Receptors, LDL ; biosynthesis ; genetics ; Stilbenes ; isolation & purification ; pharmacology ; Triglycerides ; blood ; metabolism