Relationship between CD40 ligand expression and B type natriuretic peptide levels in patients with chronic heart failure.

BACKGROUND: Inflammation plays a pathogenic role in the development of chronic heart failure (CHF). Increasing evidence shows that CD40-CD40 ligand (CD40L) interaction plays a pathogenic role in inflammatory disorders. We assessed whether CD40 ligand expression was abnormal in patients with CHF. METHODS: Twenty normal controls and 86 patients with CHF were investigated. The expression of CD40L on platelets was analyzed by indirect-immunofluorescence flow cytometry, and the soluble CD40L (sCD40L) level was determined by a commercially available enzyme-linked immunosorbent assay (ELISA). B type natriuretic peptide (BNP) was measured by radioimmunoassay. RESULTS: All patients with CHF showed a significant increased expression of CD40L (32.3+/-13.9 MFI) on platelets and sCD40L levels (20.5+/-8.6 microg/l) compared with controls(p<0.0001). CD40L expression on platelets and sCD40L levels positively correlated with New York Heart Association (NYHA) functional class, left ventricular ejection fraction and BNP levels in CHF. CONCLUSIONS: Patients with CHF showed increased expression of CD40L system, which may create a pathogenic role in the development and progression of CHF.

The clinical implications of increased OX40 ligand expression in patients with acute coronary syndrome.

BACKGROUND: Increasing evidence show that OX40 ligand (OX40L), also known as tumor necrosis factor superfamily member 4 (TNFSF4), plays an important role in the pathogenesis of atherosclerosis. We investigated whether expression levels of soluble OX40L in serum and of membrane OX40L on platelets were related to serum concentrations of matrix metalloproteinases (MMPs) and stability of coronary atherosclerotic plaque in patients with acute coronary syndrome (ACS). METHODS: We included healthy controls (n=30), patients with stable angina (SA) (n=40) and patients with ACS, including unstable angina (UA) (n=70) and acute myocardial infarction (AMI) (n=40). The expression of OX40L on platelets (pOX40L) was analyzed with flow cytometry whereas serum concentrations of soluble OX40L (sOX40L), MMP-9 and MMP-3 were determined with ELISA. All coronary stenoses with >or=30% diameter reduction were assessed by angiographic coronary stenosis morphology. RESULTS: The expression of OX40L on platelets were significantly higher in patients with ACS (61.5+/-11.5) compared with healthy controls (28.9+/-7.4) or with the group of patients with SA (31.2+/-8.1) (mean fluorescence intensity+/-SD) (p<0.001). Similarly, we observed higher sOX40L concentrations in patients with ACS (34.6+/-9.3) compared with controls (10.2+/-4.7) or patients with SA (11.4+/-5.8) (ng/ml+/-SD) (p<0.001). Serum MMP-3 and MMP-9 levels in patients were two times greater than those in the control group. A positive correlation was observed between OX40L expression on platelets and MMP-9 and MMP-3 serum concentrations. OX40L expression on platelets were furthermore correlated with soluble OX40L in serum and with complex coronary stenoses (r1=0.61, r2=0.57, p<0.001). CONCLUSION: Patients with ACS show increased OX40L system (pOX40L and sOX40L) expression which may create a proinflammatory milieu for aggravating the development of atherosclerosis, and may be a valuable marker for predicting the severity of ACS.

Cardiac resynchronization therapy for heart failure induced by left bundle branch block after transcatheter closure of ventricular septal defect.

A 54-year-old female patient with congenital heart disease had a persistent complete left bundle branch block three months after closure by an Amplatzer ventricular septal defect occluder. Nine months later, the patient suffered from chest distress, palpitation, and sweating at daily activities, and her 6-min walk distance decreased significantly (155 m). Her echocardiography showed increased left ventricular end-diastolic diameter with left ventricular ejection fraction of 37%. Her symptoms reduced significantly one week after received cardiac resynchronization therapy. She had no symptoms at daily activities, and her echo showed left ventricular ejection fraction of 46% and 53%. Moreover, left ventricular end-diastolic diameter decreased 6 and 10 months after cardiac resynchronization therapy, and 6-min walk distance remarkably increased. This case demonstrated that persistent complete left bundle branch block for nine months after transcatheter closure with ventricular septal defect Amplatzer occluder could lead to left ventricular enlargement and a significant decrease in left ventricular systolic function. Cardiac resynchronization therapy decreased left ventricular end-diastolic diameter and increased left ventricular ejection fraction, thereby improving the patient's heart functions.

Bisoprolol reverses epinephrine-mediated inhibition of cell emigration through increases in the expression of ß-arrestin 2 and CCR7 and PI3K phosphorylation, in dendritic cells loaded with cholesterol.

The effect of bisoprolol on dendritic cell (DC) migration was investigated, including the analysis of protein expression, cytokine secretion and activation of the PI3K-pathway. The chemotactic cell numbers in cholesterol-loaded DCs treated with epinephrine were significantly decreased by 26.66±6.29% (6h), 35.67±2.91% (12h) and 29.33±1.09% (24h). This effect was significantly reversed by 46.00±10.65% (6h), 64.25±6.77% (12h) and 55.74±5.51% (24h) when bisoprolol and epinephrine were both present. In cholesterol-loaded DCs, treatment with epinephrine significantly increased AR-ß1 protein expression by 56.99±4.87%, but inhibited ß-arrestin 2 and CCR7 protein expression by 30.51±4.22% and 25.31±0.04%, respectively. These effects were reversed by bisoprolol by 36.87±4.40%, 41.47±3.95% and 30.14±0.54%, respectively. TNF-α and MMP9 levels were decreased by 68.33±4.00% and 39.57±9.21% in cholesterol-loaded DCs treated with epinephrine. In contrast, when bisoprolol and epinephrine were administered together, the secretion of these proteins was significantly increased by 233.81±37.06 % and 76.66±14.21%, respectively. Treatment with epinephrine decreased PI3K-phosphorylation by 31.88±2.79%, 40.24±5.69% and 30.93±4.66% at 15, 30 and 60min, respectively, whereas the effect of epinephrine on the expression of phosphorylated PI3K was reversed by 49.49±12.12%, 70.93±16.14% and 47.62±6.00%, respectively, when cells were treated with both bisoprolol and epinephrine. Wortmannin inhibited the effects of bisoprolol on PI3K-phosphorylation (38.63±6.12%), the expression of CCR7 (23.4±2.72%), the secretion of TNF-α (69.46±4.48%) and MMP9 (43.15±4.63%), and the number of chemotactic cells (36.84±5.22%). This is the first study to establish a signaling pathway, epinephrine-AR-ß1-ß-arrestin2-PI3K-MMP9/CCR7, which plays a critical role in the migration of DCs.

Losartan inhibited expression of matrix metalloproteinases in rat atherosclerotic lesions and angiotensin II-stimulated macrophages.

AIM: To explore whether the angiotensin II (Ang II) receptor 1 (AT1) antagonist, losartan could reduce activity and expression of matrix metalloproteinases (MMPs) in rat atherosclerotic plaques. METHODS: Male Wistar-Kyoto rats were ip injected a single dose of vitamin D3 600 kU x kg(-1) x month(-1) and fed an atherogenic diet for 4 months to induce experimental atheroma. Then either placebo or losartan 50 mg x kg(-1) x d(-1) was administered in rats for another 2 months. In vitro, the effect of losartan 0.1-10 micromol/L on the expression of MMP-2 and MMP-9 was investigated in Ang II-stimulated rat peritoneal macrophages. The expression and activity of MMP-2 and MMP-9 were monitored by Western blot, RT-PCR, and SDS-PAGE zymography analysis. RESULTS: High levels of MMP-2 and MMP-9 were expressed in rat atherosclerotic lesions. Losartan significantly reduced the activity and expression of MMP-2 and MMP-9 compared with the placebo group (MMP-2, 5861+/-539 vs 8991+/-965, P<0.05; MMP-9,10527+/-1002 vs 14623+/-2462, P<0.01). In cultured rat peritoneal macrophages, Ang II 0.1 micromol/L elicited an increase in MMP-2 and MMP-9 activity and expression that were prevented by losartan in a dose-dependent manner (P<0.01). But the AT2 receptor antagonist PD123319 had no effect. CONCLUSION: Losartan reduced the expression and activity of MMP-2 and MMP-9 in rat atherosclerotic lesions. The anti-atherogenic effects of losartan were due to the direct inhibition of Ang II bioactivity.