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Published on: July 10, 2019
Rapamycin attenuates vascular wall inflammation and progenitor cell promoters after angioplasty
Thomas G Nührenberg1, Rainer Voisard, Felicitas Fahlisch
1I. Medizinische Klinik und Deutsches Herzzentrum, München, Germany.
Abstract:
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.
Insights
Rapamycin suppresses gene expression linked to inflammation and cell recruitment after vascular injury. This mechanism may explain its effectiveness in preventing restenosis by reducing leukocyte and hematopoietic progenitor cell infiltration.
Area of Science:
- Vascular Biology
- Pharmacology
- Molecular Medicine
Background:
- Neointima formation after angioplasty contributes to restenosis.
- Rapamycin is known to reduce neointima formation but its molecular targets are unclear.
- The impact of rapamycin on gene expression during neointima formation requires investigation.
Purpose of the Study:
- To systematically analyze the effect of rapamycin on gene expression during neointima formation.
- To identify transcriptional programs regulated by rapamycin in response to vascular injury.
- To elucidate the molecular mechanisms underlying rapamycin's anti-restenotic effects.
Main Methods:
- Human renal artery segments were subjected to angioplasty and cultured ex vivo.
- Segments were treated with rapamycin (100 ng/ml) or vehicle for 21 or 56 days.
- Comprehensive gene expression analysis was performed on 2312 genes.
Main Results:
- Mechanical injury induced a proinflammatory and proadhesive gene expression pattern, involving chemokines and cytokines.
- Genes related to leukocyte and hematopoietic progenitor cell (HPC) recruitment and stimulation were upregulated post-injury.
- Rapamycin significantly suppressed this coordinated gene expression pattern, including downregulation of metabolic and apoptotic genes.
Conclusions:
- Mechanical vascular injury triggers an intrinsic inflammatory and proadhesive gene expression program in the vessel wall.
- This program facilitates the recruitment of leukocytes and HPC, potentially driving restenosis.
- Rapamycin inhibits these injury-induced transcriptional changes, likely reducing leukocyte and HPC recruitment and contributing to its anti-restenotic efficacy.
