Tien-Ping Tsao

Carvedilol, a new antioxidative β-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-κB activity

Objective: The activation of T lymphocytes contributes to the inflammatory process of atherosclerosis. Here we examined the effects of carvedilol, a new β-blocker containing an antioxidative property, on the activation of T cells. Methods: Human peripheral blood T cells were negatively selected from whole blood. Cytokines were measured by ELISA. The NF-κB and related protein activity was determined by electrophoretic mobility shift assays, Western blotting, kinase assays and transfection assays. Results: Carvedilol was nontoxic at concentrations ≦10 μM, however, higher dosages (≥20 μM) induced T cell apoptosis. We demonstrated that carvedilol inhibited cytokine production from various stimuli-activated T cells. Carvedilol also suppressed the expression of T cell activation markers, including CD25, CD69 and CD71. Molecular investigation indicated that carvedilol specifically downregulated NF-κB but not activator protein 1 DNA-binding activity in activated T cells. The inhibitory effect was likely due to its antioxidative property. Meanwhile, carvedilol prevented stimuli-induced IκBα degradation. Such an effect was mediated through the inhibition of IκBα kinase activity. The inhibitory specificity on NF-κB by carvedilol was also demonstrated in transfection assays. Conclusions: Our results demonstrated a novel therapeutic mechanism of carvedilol in atherosclerosis, namely the inhibition of T cell activation via downregulating NF-κB activity.

Down-regulation of c-jun N-terminal kinase-activator protein-1 signaling pathway by Ginkgo biloba extract in human peripheral blood T cells.

The activation of T lymphocytes contributes to inflammatory process of cardiovascular and cerebrovascular diseases. We investigated the effects of the extract of Ginkgo biloba (EGb), an ancient plant preserving antioxidant property, on phorbol 12-myristate 13-acetate+ionomycin or anti-CD3+anti-CD28 monoclonal antibodies-activated T cells. Human peripheral blood T cells were negatively selected from whole blood. Cytokines were measured by ELISA, cell surface markers by flow cytometry and the activities of transcription factors and kinases were determined by electrophoresis mobility shift assays, kinase assays and transfection assays. We showed that EGb inhibited several cytokines, including tumor necrosis factor-alpha, interleukin (IL)-2, IL-4 and interferon-gamma production from activated T cells. Electrophoresis mobility shift assay analysis indicated that EGb down-regulated activator protein-1 (AP-1) but not nuclear factor kappa B DNA-binding activity. In addition, EGb inhibited c-jun N-terminal kinase but not extracellular signal regulated protein kinase activity. The inhibitory specificity on AP-1 by EGb was also demonstrated in transfection assays. The inhibition of AP-1 signaling pathway in T cells by EGb provides a support for its efficacy in cardiovascular and cerebrovascular diseases and raises a therapeutic potential for this drug in activated T cell-mediated pathologies.

Modulation of human T cells signaling transduction by lovastatin

Statins are applied clinically to treat hypercholesterolemia and proposed to have some kinds of anti-inflammatory properties for reducing the incidence of atherosclerosis-related cardiovascular events. However, it was rarely known about statins on the signal transduction on human primary T cells. To gain insight into the mechanism of statins on human T cells, we investigated the effects of both lovastatin and atorvastatin on activated human primary T cells. The human primary T cells from the blood of normal human beings were isolated. We found that lovastatin, but not atorvastatin, can dose-dependently inhibit cytokine production such as interleukin-2, interleukin-4, and interferon-gamma from activated human T cells. Neither lovastatin nor atorvastatin can regulate the TNF-alpha production on both activated human T cells and monocytes. Molecular investigation was performed that lovastatin, but not atorvastatin, could down-regulate both activator protein-1 and NF-kappaB DNA binding activities, assessed by electrophoretic mobility shift assay. Our observations may extend potential and differential therapeutic mechanisms of lovastatin with cell-mediated capacity to prevent or treat some of inflammation related diseases.

Irbesartan inhibits human T-lymphocyte activation through downregulation of activator protein-1

Irbesartan is a promising antihypertensive drug with beneficial effects on atherosclerotic processes. In the progression of atherosclerosis, human T‐lymphocytes play an important role, but it is not yet known how irbesartan modulates human T‐lymphocytes activation. To gain insight into the mechanisms by which irbesartan acts, we investigated its effects on human T‐lymphocytes. Primary human T‐lymphocytes were isolated from whole blood. Cytokines were determined by ELISA. Activator protein‐1 (AP‐1) and related protein activities were determined by electrophoretic mobility shift assays, kinase assays, Western blotting and transfection assays. Irbesartan inhibited the production of both tumor necrosis factor‐alpha and interferon‐gamma by activated T‐cells, especially at therapeutic concentrations. Further investigation at the molecular level indicated that the inhibition of activated human T‐lymphocytes specifically correlated with the downregulation of AP‐1 DNA‐binding activity. In the Jurkat T‐cell line, irbesartan also inhibited AP‐1 transcriptional activity. Finally, we revealed that irbesartan is unique in its ability to inhibit the activation of both c‐Jun NH2‐terminal protein kinase and p38 MAPK. Our studies show that irbesartan may modulate inflammation‐based atherosclerotic diseases through a cell‐mediated mechanism involving suppression of human T‐lymphocytes activation via downregulation of AP‐1 activity.

Carvedilol differentially regulates cytokine production from activated human peripheral blood mononuclear cells

Chronic inflammation is one of the important mechanisms involved in atherosclerosis formation. The activated monocytes and their secreted cytokines contribute significantly to this inflammatory process. Here we examined the effects of carvedilol, a recently introduced cardio-protective alpha-1- and beta-receptor blocker, on cytokine production from various stimuli-activated human immune effector cells. By ELISA analysis, we showed that carvedilol inhibited interferon-gamma (IFN-γ), but enhanced interleukin (IL)-12 production in phytohemagglutinin (PHA)- and concanavalin A (ConA)-stimulated human peripheral blood mononuclear cells (PBMCs). The production of tumor necrosis factor-alpha (TNF-α) was marginally affected. When purified monocytes were examined, we observed the consistent up-regulation of IL-12 production while both IL-10 and TNF-α were unaffected or marginally down-regulated, respectively, by carvedilol. In agreement with the observation in monocytes, the production of IL-12 from activated macrophages was also up-regulated by carvedilol. We concluded that carvedilol might mediate its therapeutic effects through differentially regulating cytokine production from activated mononuclear cells, including at least monocytes and macrophages.

Comparison of intracoronary adenosine and isosorbide dinitrate on no-reflow/slow flow during rotational atherectomy.

Objective — To compare the effect of intracoronary adenosine and isosorbide dinitrate (ISDN) on no-reflow/slow flow during high-speed rotational atherectomy (HSRA) in patients with complex coronary artery disease (CAD). Methods and results — Medical records from consecutive patients diagnosed with complex CAD between November 2002 and March 2006 who underwent HSRA at the Tri-Service General Hospital, National Defence Medical Centre in Taipei, Taiwan, were included in this study. Patients in the adenosine group (n = 32) received a 50 mg intracoronary adenosine bolus prior to the initiation of burr rotation and during each ablation. Patients in the ISDN group (n = 58) received a 0.5 mg intracoronary ISDN bolus at comparable time points. Angiographic success was achieved in 100% of patients in the adenosine group and 98.3% (57/58) in the ISDN group.The procedural success rates were 96.9% (31/32) in the adenosine group and 89.7% (52/58) in the ISDN group. One patient (3.1%) from the adenosine group and six patients (10.3%) from the ISDN group experienced no-reflow/slow flow (P = 0.414). No in-hospital mortality occurred and target vessel revascularization was unnecessary. Conclusions — Intracoronary administration of either adenosine or ISDN during HSRA appears safe and administration of either agent may be effective in decreasing the incidence of no-reflow/slow flow during HSRA. Further large, prospective, randomized, placebo-controlled trials are required.

Stenting for coronary intervention-related dissection of the left main coronary artery with extension to the aortic root: a case report.

Retrograde aortocoronary dissection is a rare but devastating complication of coronary angioplasty. It occurs most frequently in the right coronary artery, rarely in the left. This is a case report of an aortic dissection complicated by coronary angioplasty of the left circumflex artery. Stenting of the left main coronary artery successfully sealed the entry point of dissection.