Correlation between coronary artery lesion quantitative score and OSAHS and relative risk factors.

OBJECTIVE: The purpose of this study was to investigate the relationship of obstructive sleep apnea hypopnea syndrome (OSAHS) with coronary artery lesion quantitative score Syntax Score (SX score) and risk factors for coronary heart disease (CHD). PATIENTS AND METHODS: A total of 115 patients with OSAHS admitted to the Department of Cardiology in our hospital from January 2011 to June 2015 were selected. Philips Respironics Alice 5 Polysomnography was used for sleep monitoring. The patients were divided into mild group (n=32), moderate group (n=36) and severe group (n=47) according to apnea hypopnea index (AHI). Coronary angiography was performed for the patients, and SX score was calculated. Fasting venous blood was extracted from all patients with OSAHS and sent for detection of blood routine, coagulation, liver and kidney function, blood lipid and other indexes, and all patients received color Doppler echocardiography. RESULTS: The body weight and body mass index (BMI) of patients with OSAHS in severe group were higher than those in the mild group and moderate group (p<0.05). The content of fibrinogen (FIB) of patients in severe group was higher than that in mild group (p<0.01). The levels of total cholesterol (TC) (p<0.05), blood uric acid (p<0.05), and serum creatinine (p<0.01) of patients in the severe group were significantly higher than those in mild group and moderate group, but there were no differences between mild group and moderate group (p>0.05). Echocardiography suggested that the left atrium diameter 1 (LAD) and pulmonary artery pressure (PAP) of patients in severe group were larger than those in the mild group and moderate group (p<0.01), and the right ventricle anteroposterior diameter (RVD) in the mild group was smaller than those in the moderate group (p<0.05) and severe group (p<0.01). The score of patients with OSAHS in the severe group was higher than those in the mild group and moderate group (p<0.01), and SX score was increased with AHI (r=0.416, p<0.01). Logistic regression analysis showed that AHI and SX score could not be used as indicators to judge the prognosis of patients. CONCLUSIONS: There is a positive correlation between AHI and SX score in patients with OSAHS, indicating that with the aggravation of respiratory sleep disorder, SX score is increased significantly and the severity of coronary artery lesion is increased accordingly.

Rosuvastatin promotes the differentiation of peripheral blood monocytes into M2 macrophages in patients with atherosclerosis by activating PPAR-γ.

OBJECTIVE: To evaluate M2 marker changes in human circulating monocytes before and after rosuvastatin treatment, and to investigate the effects of rosuvastatin on the differentiation of monocytes into M2 macrophages by activating peroxisome proliferator-activated receptor-γ (PPAR-γ). PATIENTS AND METHODS: A total of 20 patients was administrated with rosuvastatin. The human peripheral blood mononuclear cells (PBMCs) were extracted by Ficoll-Hypaque density gradient centrifugation method. PPAR-γ, CD206 and CD163 mRNA levels were detected by Real-time polymerase chain reaction (RT-PCR). The total content of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), PPAR-γ, extracellular signal-regulated kinase (ERK) and p38 Mitogen-activated protein kinase (MAPK) and the contents of phosphorylated ERK and p38 MAPK were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The expression levels of CD206, Interleukin 10 (IL-10), and chemokine (C-C motif) ligand 18 (CCL18) were significantly improved by rosuvastatin. The expression level of PPAR-γ in circulating monocytes was also distinctly up-regulated through the treatment with rosuvastatin. After rosuvastatin therapy, PPAR-γ mRNA expression was unceasingly increased with time prolonging. The tendency of mRNA level of aP2 was the same as that of PPAR-γ. In vitro experiments indicated that in M2 macrophages, rosuvastatin could enhance the decrease of CD163 expression level induced by interleukin 4 (IL-4). M1 macrophages cultured by supernatant that was used to culture M2 macrophages could significantly inhibit TNF-α and MCP-1 expressions. Rosuvastatin could remarkably induce the phosphorylation of p38 MAPK, but the effect on ERK1/2 was not obvious. CONCLUSIONS: Our results confirmed expressions of M2 markers in human circulating peripheral blood monocytes after rosuvastatin therapy. Both in vivo and in vitro experiments proved that rosuvastatin can induce the expression and activation of PPAR-γ in human monocytes, resulting in the differentiation of monocytes into M2 macrophages.

Research on clinical value of galectin-3 in evaluating the prognosis of acute heart failure.

OBJECTIVE: To investigate the clinical value of galectin-3 in the prognosis evaluation of acute heart failure. PATIENTS AND METHODS: A total of 316 patients treated in Suzhou Kowloon Hospital were enrolled into this study and followed up for 1 year. Venous blood during the onset was collected for examinations of blood routine, blood biochemistry, N-terminal B-type pro-brain natriuretic peptide (NT-proBNP), galectin-3 and other indexes. Cardiovascular events (CV events) include the re-admission or death due to the recent acute episode of chronic heart failure. RESULTS: The concentrations of NT-proBNP and galectin-3 in the CV event group were significantly increased compared with those in non-CV event group (p<0.001). Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) of NT-proBNP in predicting CV events of patients with acute heart failure within 1 year after discharge was 0.816 and that of galectin-3 was 0.847. Kaplan-Meier survival curve analysis showed that risks of CV events of patients with the NT-proBNP concentration >3013.21 pg/mL and galectin-3 concentration >17.15 ng/mL within 1 year after discharge were significantly higher than those in other groups (p<0.001). CONCLUSIONS: Galectin-3 can be used as a biomarker for the prognosis evaluation of acute heart failure, and its combined analysis can increase the predictive value of NT-proBNP.

Valproic acid-induced increase in carnitine acetyltransferase in rat hepatocytes is not due to an induction of peroxisomes.

Valproic acid induced a dose-dependent increase in carnitine acetyltransferase (CAT) activity in rat hepatic mitochondrial fractions isolated by differential centrifugation. An increase in CAT and carnitine palmitoyltransferase (CPT) also occurred in cultured rat hepatocytes in a concentration-and time-dependent fashion. A maximal increase of 8-fold in the activity of CAT and 2-fold in the activity of CPT was induced by 3 mM valproic acid in 72 h. Valproic acid had no effect on cytochrome P-450 levels in cultured rat hepatocytes. Electron-microscopic examination of rat hepatocytes showed that there was no increase in the number of peroxisomes but there was a marked proliferation of mitochondria in parallel with an increase in glutathione level and succinic dehydrogenase in the liver cells after incubation with valproic acid in vitro.

Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein.

The Rho-family GTPase, Cdc42, can regulate the actin cytoskeleton through activation of Wiskott-Aldrich syndrome protein (WASP) family members. Activation relieves an autoinhibitory contact between the GTPase-binding domain and the carboxy-terminal region of WASP proteins. Here we report the autoinhibited structure of the GTPase-binding domain of WASP, which can be induced by the C-terminal region or by organic co-solvents. In the autoinhibited complex, intramolecular interactions with the GTPase-binding domain occlude residues of the C terminus that regulate the Arp2/3 actin-nucleating complex. Binding of Cdc42 to the GTPase-binding domain causes a dramatic conformational change, resulting in disruption of the hydrophobic core and release of the C terminus, enabling its interaction with the actin regulatory machinery. These data show that 'intrinsically unstructured' peptides such as the GTPase-binding domain of WASP can be induced into distinct structural and functional states depending on context.

Structure and mutagenesis of the Dbl homology domain.

Guanine nucleotide exchange factors in the Dbl family activate Rho GTPases by accelerating dissociation of bound GDP, promoting acquisition of the GTP-bound state. Dbl proteins possess a approximately 200 residue catalytic Dbl-homology (DH) domain, that is arranged in tandem with a C-terminal pleckstrin homology (PH) domain in nearly all cases. Here we report the solution structure of the DH domain of human PAK-interacting exchange protein (betaPIX). The domain is composed of 11 alpha-helices that form a flattened, elongated bundle. The structure explains a large body of mutagenesis data, which, along with sequence comparisons, identify the GTPase interaction site as a surface formed by three conserved helices near the center of one face of the domain. Proximity of the site to the DH C-terminus suggests a means by which PH-ligand interactions may be coupled to DH-GTPase interactions to regulate signaling through the Dbl proteins in vivo.

Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott-Aldrich syndrome' protein.

The Rho-family GTP-hydrolysing proteins (GTPases), Cdc42, Rac and Rho, act as molecular switches in signalling pathways that regulate cytoskeletal architecture, gene expression and progression of the cell cycle. Cdc42 and Rac transmit many signals through GTP-dependent binding to effector proteins containing a Cdc42/Rac-interactive-binding (CRIB) motif. One such effector, the Wiskott-Aldrich syndrome protein (WASP), is postulated to link activation of Cdc42 directly to the rearrangement of actin. Human mutations in WASP cause severe defects in haematopoletic cell function, leading to clinical symptoms of thrombocytopenia, immunodeficiency and eczema. Here we report the solution structure of a complex between activated Cdc42 and a minimal GTPase-binding domain (GBD) from WASP. An extended amino-terminal GBD peptide that includes the CRIB motif contacts the switch I, beta2 and alpha5 regions of Cdc42. A carboxy-terminal beta-hairpin and alpha-helix pack against switch II. The Phe-X-His-X2-His portion of the CRIB motif and the alpha-helix appear to mediate sensitivity to the nucleotide switch through contacts to residues 36-40 of Cdc42. Discrimination between the Rho-family members is likely to be governed by GBD contacts to the switch I and alpha5 regions of the GTPases. Structural and biochemical data suggest that GBD-sequence divergence outside the CRIB motif may reflect additional regulatory interactions with functional domains that are specific to individual effectors.