ABSTRACT
Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.
Subject(s)
Atherosclerosis/enzymology , Ubiquitin-Protein Ligases , Ubiquitination , Endothelial Cells/metabolism , Humans , Inflammation , Lipid Metabolism , Myocytes, Smooth Muscle/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
BACKGROUND: Recent studies have suggested that pregnancy-associated plasma protein-A (PAPP-A) is involved in the pathogenesis of atherosclerosis. This study aim is to investigate the role and mechanisms of PAPP-A in reverse cholesterol transport (RCT) and inflammation during the development of atherosclerosis. MethodsâandâResults: PAPP-A was silenced in apolipoprotein E (apoE-/-) mice with administration of PAPP-A shRNA. Oil Red O staining of the whole aorta root revealed that PAPP-A knockdown reduced lipid accumulation in aortas. Oil Red O, hematoxylin and eosin (HE) and Masson staining of aortic sinus further showed that PAPP-A knockdown alleviated the formation of atherosclerotic lesions. It was found that PAPP-A knockdown reduced the insulin-like growth factor 1 (IGF-1) levels and repressed the PI3K/Akt pathway in both aorta and peritoneal macrophages. The expression levels of LXRα, ABCA1, ABCG1, and SR-B1 were increased in the aorta and peritoneal macrophages from apoE-/-mice administered with PAPP-A shRNA. Furthermore, PAPP-A knockdown promoted RCT from macrophages to plasma, the liver, and feces in apoE-/-mice. In addition, PAPP-A knockdown elevated the expression and secretion of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), tumor necrosis factor-α, and interleukin-1ß through the nuclear factor kappa-B (NF-κB) pathway. CONCLUSIONS: The present study results suggest that PAPP-A promotes the development of atherosclerosis in apoE-/-mice through reducing RCT capacity and activating an inflammatory response.
Subject(s)
Atherosclerosis/etiology , Cholesterol/metabolism , Inflammation/etiology , Pregnancy-Associated Plasma Protein-A/physiology , Animals , Aorta/metabolism , Aorta/pathology , Atherosclerosis/pathology , Biological Transport , Female , Humans , Lipid Metabolism/drug effects , Macrophages/metabolism , Mice , Mice, Knockout, ApoE , NF-kappa B/metabolism , Pregnancy , Pregnancy-Associated Plasma Protein-A/pharmacologyABSTRACT
This study was aimed to investigate the expression of RHBDD1 gene in patients with chronic myeloid leukemia (CML) and explore its clinical significance. The relative expression levels of RHBDD1 in bone marrow mononuclear cells of healthy controls and CML patients were detected by using real time PCR. The results showed that the expression level of RHBDD1 in CML patients was significantly higher than that in healthy controls. The expression level of RHBDD1 in CML patients with negative BCR/ABL p210 was remarkably higher than that in patients with positive BCR/ABL p210. In patients ≥ 50 years old RHBDD1 expression was lower than the patients < 50 years old. There were no significant relation of RHBDD1 expression with sex of patients. It is concluded that RHBDD1 gene may be involved in the pathogenesis and progression of CML, particularly reflects in the pathogenesis of the patients with negative BCR/ABL p210.
Subject(s)
Female , Humans , Male , Middle Aged , Bone Marrow Cells , Metabolism , Pathology , Case-Control Studies , Gene Expression , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Genetics , Metabolism , Pathology , Serine Endopeptidases , Genetics , MetabolismABSTRACT
To unravel the relation of HLA-DRB1*15 with childhood acute lymphoblastic leukemia (ALL), 162 childhood patients with ALL were selected for this investigation. 1 000 normal umbilical cord blood samples were used as control.HLA-DRB1*15 and HLA-DRB5* were typed by polymerase chain reaction (PCR) analysis. The relation of HLA-DRB1*15 with childhood ALL was studied by calculating the chi-square test and relative risk. The results showed that the antigen frequencies and allele frequencies of HLA-DRB1*15 in childhood patients with ALL were 40.12% and 22.62% respectively, while the antigen frequencies and allele frequencies of HLA-DRB1*15 in control were 30.80% and 16.81% respectively, there were significant difference between them (chi(2) = 5.560, p = 0.018, RR = 1.506). In conclusion, the antigen frequencies and allele frequencies of HLA-DRB1*15 in childhood patients with ALL were higher than those in control, so the HLA-DRB1*15 gene is one of the genetic risk factors for childhood ALL. These preliminary data may be useful for further study on the pathogenesis of childhood ALL.
