Pioglitazone suppresses the lipopolysaccharide-induced production of inflammatory factors in mouse macrophages by inactivating NF-kappaB.

TZDs (thiazolidinediones) are prescribed as anti-Type II diabetes drugs, but little is known regarding whether TZDs regulate the expression of sPLA2 (secretory phospholipase A2) in macrophages. We have investigated the effects of pioglitazone on LPS (lipopolysaccharide)-induced production of TNF-alpha (tumour necrosis factor alpha), sPLA2-V and -X (groups V and X sPLA2) in RAW 264.7 macrophages. TNF-alpha, sPLA2-V and -X mRNA and protein expression were determined by RT-PCR (reverse transcriptase-PCR) and Western blot analysis, respectively. The activity of NF-kappaB (nuclear factor kappaB) was determined by Western blot and confocal microscopy. LPS induced TNF-alpha, sPLA2-V and sPLA2-X mRNA and protein expression. Pretreatment with 10 mumol/l pioglitazone significantly suppressed LPS-induced TNF-alpha, sPLA2-V and sPLA2-X mRNA and protein expression. LPS induced NF-kappaB expression and translocation in the nucleus, but the inductive effects were inhibited by pioglitazone. Our findings indicate that pioglitazone inhibits production of inflammatory factors induced by LPS in murine macrophage cells by inactivating NF-kappaB. Pioglitazone appears to play an anti-inflammatory role in the atherosclerotic process.

Circulating secretory type IIA phospholipase A2, lipoprotein (a) and soluble cellular adhesion molecule levels in patients with angina pectoris.

OBJECTIVES: To examine the plasma levels of secretory type IIA phospholipase A2 (sPLA(2)-IIA), lipoprotein (a) [Lp(a)], soluble intercellular adhesion molecule-1 (sICAM-1) and soluble platelet endothelial CAM-1 (sPECAM-1), as well as ICAM-1 (K469E) and PECAM-1 (Leu125Val) gene polymorphisms, in patients with unstable angina pectoris (UAP) and stable AP (SAP). DESIGN AND METHODS: We enrolled 75 patients with SAP, 72 with UAP and 80 controls without angina. Blood samples were obtained before angiography. RESULTS: The concentrations of sPLA(2)-IIA, sICAM-1 and sPECAM-1 were higher for UAP patients than for SAP patients and controls, and the level of Lp(a) was higher for UAP patients than for controls. Lp(a) and sPLA(2)-IIA levels were significantly correlated, and high plasma Lp(a) level (> or =300 mg/L) was an independent risk factor for angina. CONCLUSION: Lp(a) may play an important role in the development of angina. Further research should investigate the role of sPLA(2)-IIA, sICAM-1 and sPECAM-1 in UAP.

Platelet-endothelial cell adhesion molecule-1 gene polymorphism and its soluble level are associated with severe coronary artery stenosis in Chinese Singaporean.

OBJECTIVES: Platelet-endothelial cell adhesion molecule-1 (PECAM-1) mediates the transendothelial migration of circulating leukocytes, a characteristic change in vascular inflammation leading to atherosclerotic plaque development. We hypothesized that genetic variation and soluble level of PECAM-1 could be associated with coronary artery disease (CAD). DESIGN AND METHODS: We analyzed two single nucleotide polymorphisms (SNPs) of PECAM-1 gene C+373G (Leu125Val) at exon 3, which encodes the first extracellular (Ig)-like domain that mediates the homophilic binding of PECAM-1, and G+1688A (Ser563Asn) at exon 8 in 144 angiographically documented (> or =70% stenosis) patients with CAD and 150 age- and sex-matched controls in the Chinese population in Singapore, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy. Level of plasma soluble PECAM-1 (sPECAM-1) was measured by ELISA. RESULTS: The Leu125Val polymorphism was associated with CAD (P < 0.01). Also, the level of sPECAM-1 is was found to be elevated in CAD patients (P = 0.005). Moreover, subjects with the homozygous GG genotype of the Leu125Val polymorphism had higher sPECAM-1 levels (P = 0.005). The level of sPECAM-1 was further correlated to soluble platelet selectin (sP-selectin, also measured by ELISA), platelet count, and total white blood cell count (WBC), suggesting that platelets are a major source of sPECAM-1 and platelet activation and inflammation may contribute to PECAM-1 elevations in CAD patients. CONCLUSION: The Leu125Val polymorphism of PECAM-1 and the level of sPECAM-1 are associated with CAD in Chinese in Singapore. The level of sPECAM-1 is also associated with platelet activation and inflammation and correlated to the Leu125Val polymorphism. Our data suggest that PECAM-1 plays an important role in the development of atherosclerosis.

Markers of low-grade inflammation and soluble cell adhesion molecules in Chinese patients with coronary artery disease.

BACKGROUND: Inflammation plays an important role in atherosclerosis. Markers of low-grade chronic inflammation, such as C-reactive protein (CRP) and soluble cell adhesion molecules (sCAMs), have been associated with coronary artery disease (CAD). OBJECTIVE: To evaluate the significance of inflammatory markers as novel risk factors for CAD in the Chinese population. METHODS: High-sensitivity CRP (hs-CRP); sCAMs, including vascular cell adhesion molecule-1 (sVCAM-1), intercellular cell adhesion molecule-1 (sICAM-1), P-selectin (sP-selectin) and E-selectin (sE-selectin); and white blood cell (WBC) count were measured in 170 angiographically defined CAD patients (70% or greater stenosis affecting at least one vessel) and 177 healthy control subjects in the Chinese population in Singapore. RESULTS: The levels of hs-CRP, sVCAM-1 and sP-selectin, and the WBC count were higher in CAD patients than in control subjects (P<0.001, P<0.05, P<0.05 and P<0.001, respectively). There were no significant differences in the levels of sICAM-1 and sE-selectin between the two groups. Patients with unstable angina or myocardial infarction had higher levels of hs-CRP, and higher WBC and monocyte counts than those with stable angina or atypical chest pain (all P<0.05). The level of sP-selectin in patients with multivessel disease was higher than in those with single-vessel disease (P<0.05). Overall, the levels of hs-CRP and sCAMs showed a significant correlation with the lipid profile and the WBC count. CONCLUSIONS: The present study suggests that inflammatory markers, including hs-CRP and WBC count, together with sP-selectin and sVCAM-1, could serve as markers of atherogenesis in Chinese patients with CAD, with potential diagnostic and therapeutic implications.