Rapamycin attenuates vascular wall inflammation and progenitor cell promoters after angioplasty.
Rapamycin combines antiproliferative and antiinflammatory properties and reduces neointima formation after angioplasty in patients. Its effect on transcriptional programs governing neointima formation has not yet been investigated. Here, we systematically analyzed the effect of rapamycin on gene expression during neointima formation in a human organ culture model. After angioplasty, renal artery segments were cultured for 21 or 56 days in absence or presence of 100 ng/ml rapamycin. Gene expression analysis of 2312 genes revealed 264 regulated genes with a peak alteration after 21 days. Many of those were associated with recruitment of blood cells and inflammatory reactions of the vessel wall. Likewise, chemokines and cytokines such as M-CSF, IL-1beta, IL-8, beta-thromboglobulin, and EMAP-II were found up-regulated in response to vessel injury. Markers indicative for a facilitated recruitment and stimulation of hematopoetic progenitor cells (HPC), including BST-1 and SDF-1, were also induced. In this setting, rapamycin suppressed the coordinated proadhesive and proinflammatory gene expression pattern next to down-regulation of genes related to metabolism, proliferation, and apoptosis. Our study shows that mechanical injury leads to induction of a proinflammatory, proadhesive gene expression pattern in the vessel wall even in absence of leukocytes. These molecular events could provide a basis for the recruitment of leukocytes and HPC. By inhibiting the expression of such genes, rapamycin may lead to a reduced recruitment of leukocytes and HPC after vascular injury, an effect that may play a decisive role for its effectiveness in reducing restenosis.
Nührenberg
Thomas G
TG
I. Medizinische Klinik und Deutsches Herzzentrum, München, Germany.
Voisard
Rainer
R
Fahlisch
Felicitas
F
Rudelius
Martina
M
Braun
Jürgen
J
Gschwend
Jürgen
J
Kountides
Margaratis
M
Herter
Tina
T
Baur
Regine
R
Hombach
Vinzenz
V
Baeuerle
Patrick A
PA
Zohlnhöfer
Dietlind
D
D000368:Aged; D000800:Angioplasty, Balloon / Q000009:adverse effects*; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods / Q000706:statistics & numerical data; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006083:Graft Occlusion, Vascular / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000235:genetics / Q000517:prevention & control; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods / Q000706:statistics & numerical data; D009924:Organ Culture Techniques / Q000379:methods; D012077:Renal Artery / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D013234:Stem Cells; D015607:Stents; D013995:Time; D000267:Tissue Adhesions / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D017539:Tunica Intima / Q000378:metabolism; D001620:beta-Thromboglobulin / Q000096:biosynthesis / Q000276:immunology
D001620:beta-Thromboglobulin; D020123:Sirolimus