ABSTRACT
BACKGROUND AND OBJECTIVES: The aim of this clinical study was to evaluate the safety of local delivery of a photosensitizer followed by photodynamic therapy (PDT), to determine its effectiveness in reducing in-stent restenosis. STUDY DESIGN/PATIENTS AND METHODS: Porfimer sodium was administered via a local delivery catheter to five coronary-stent implanted lesions followed by irradiation with a pulse laser. Coronary angiography (CAG) was performed at the baseline, after the procedure and at a 6-month follow-up. RESULTS: By the 18-month clinical follow-up, no adverse events such as photodermatosis, or myocardial ischemia had occurred. At the follow-up, no coronary embolization, dissection, or aneurysmal dilatation was observed in the CAG. In-stent diameter stenosis, late loss, and loss index were 19.16+/-8.20%, 0.37+/-0.18 mm, and 0.19+/-0.12, respectively. No in-stent restenosis was observed. CONCLUSIONS: This study suggests that PDT, with local delivery of Porfimer sodium, is safe and may be a feasible technique in preventing in-stent restenosis.
Subject(s)
Coronary Restenosis/prevention & control , Dihematoporphyrin Ether/administration & dosage , Photochemotherapy , Photosensitizing Agents/administration & dosage , Stents , Aged , Animals , Coronary Angiography , Coronary Restenosis/diagnostic imaging , Coronary Stenosis/therapy , Female , Follow-Up Studies , Humans , Male , Middle Aged , Rabbits , Time FactorsABSTRACT
BACKGROUND: The beneficial effects of cerivastatin including hypolipidemic properties have been demonstrated to involve nonlipid as well as lipid mechanisms. In the present study, we examined the mechanisms underlying cerivastatin-induced growth inhibition of human aortic smooth muscle (ASM) cells. METHODS: Human ASM cells were cultured in 96-well plates with or without cerivastatin in the presence or absence of mitogen-activated protein (MAP) kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase MEK1/MEK 2 inhibitor PD98059. Cell growth was assessed by colorimetric quantitation of NADH, and cell viability was determined by trypan blue dye exclusion method. The induction of apoptosis was determined by propidium iodide (PI) staining method using flow cytometer. The activation of ERKs or c-Jun N-terminal kinases (JNKs) was determined by Western blotting using antibodies (Abs) specific for phospho-ERKs or phospho-JNKs. RESULTS: Treatment of the ASM cells with cerivastatin prevented cell growth in a concentration-dependent manner through at least induction of apoptosis. The cerivastatin-induced apoptosis was reversed by coincubation with isoprenoid [mevalonate, geranylgeranyl pyrophosphate (GGPP), and farnesyl pyrophosphate (FPP)] suggesting a role for isoprenoid in the cerivastatin-induced apoptosis. The cerivastatin cooperated with a MEK1/MEK2 inhibitor PD98059 to induce apoptosis, which appeared to correlate with down-regulation of ERK activation (phospho-ERKs expression) induced by the combination. CONCLUSION: Cerivastatin-induced blockade of ERK activation in ASM cells might result in growth inhibition including apoptosis, which might explain some aspects of the beneficial effects of cerivastatin on coronary artery disease.
Subject(s)
Aorta/pathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Mitogen-Activated Protein Kinases/drug effects , Muscle, Smooth, Vascular/drug effects , Pyridines/pharmacology , Aorta/drug effects , Apoptosis/drug effects , Blotting, Western , Cell Division/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Flow Cytometry , Humans , JNK Mitogen-Activated Protein Kinases , Mitogen-Activated Protein Kinases/metabolism , Muscle, Smooth, Vascular/pathology , Polyisoprenyl Phosphates/pharmacology , Sesquiterpenes , Terpenes/pharmacologyABSTRACT
Tumor necrosis factor (TNF) family proteins including TNF-alpha and Fas (CD95)-ligand have been implicated in the development of acute myocardial infarction (AMI). We studied whether AMI patients displayed up-regulation of another TNF family member, TNF-related-apoptosis-inducing ligand (TRAIL), on peripheral blood mononuclear cells (PBMCs). We compared expression of TRAIL on PBMCs from 26 patients in the acute phase of AMI with that on PBMCs from 16 healthy control subjects using flow cytometry and RT-PCR. In addition, expression of TRAIL protein on PBMCs from patients in the acute phase of AMI was also compared with that from the same patients 7 days later. Furthermore, we compared the expression of TRAIL protein on CD4+, CD8+, CD14+, and CD19+ cells from patients in the acute phase of AMI with that from control subjects using flow cytometry. Finally, expression of the TRAIL receptors (TRAILR)-1 and TRAILR-2 in human cardiomyocytes was examined immunohistochemically. Expression of TRAIL protein was significantly higher in the acute phase of AMI than in control subjects. Expression of TRAIL protein was significantly higher in the acute phase of AMI than 7 days later. TRAIL mRNA expression in the acute phase of AMI was higher than in control subjects. Expression of TRAIL protein on CD4+ and CD14+ cells from AMI patients was significantly higher than that from control subjects. Expression of TRAILR-1 and TRAILR-2 in human cardiomyocytes was confirmed immunohistochemically. TRAIL on infiltrating CD4 and CD146 cells may be involved in the induction of cardiomyocyte apoptosis after AMI.
