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Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases
1Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.
Abstract:
The present study was designed to investigate whether apoptosis occurs in early-stage vein grafts and to determine the mechanisms by which mechanical stress contributes to apoptosis in vascular smooth muscle cells (SMCs). Apoptosis in vessel walls of mouse vein grafts was confirmed by morphological changes and by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). TUNEL(+) cells in vein grafts 1, 4, and 8 wk postoperatively was 13%, 29%, and 21%, respectively, and apoptosis occurred mainly in veins grafted to arteries, remaining unchanged in vein-to-vein grafts. When mouse, rat, and human arterial SMCs were cultured on a flexible membrane and subjected to cyclic strain stress, apoptosis was observed in a time- and strength-dependent manner. All three types of SMCs showed apoptotic death as confirmed by TUNEL, propidium iodide, and annexin V staining. To further study the signal pathways leading to apoptosis, activities of p38, a subfamily of mitogen-activated protein kinases (MAPKs), were determined. Mechanical stress resulted in p38 MAPK activation, reaching high levels within 8 min. SB 202190, a specific inhibitor for p38 MAPKs, prevented SMC apoptosis in response to mechanical stress. SMC lines stably transfected with a dominant negative rac, an upstream signal transducer, or overexpressing MAPK phosphatase-1, a negative regulator for MAPKs, completely inhibited mechanical stress stimulated p38 activation and abolished mechanical stress-induced apoptosis. Thus, we provide solid evidence that one of the earliest events in venous bypass grafts is apoptosis, in which mechanical stress-induced p38-MAPK activation is responsible for transducing signals leading to apoptosis.-Mayr, M., Li, C., Zou, Y., Huemer, U., Hu, Y., Xu, Q. Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases.
Insights
Mechanical stress causes apoptosis in vein grafts via p38 MAPK activation. This study confirms early apoptosis in venous bypass grafts and identifies the p38 mitogen-activated protein kinase (MAPK) pathway as crucial for this process.
Area of Science:
- Cardiovascular Biology
- Cellular Biology
- Biomedical Engineering
Background:
- Vein grafts are crucial for bypass surgery, but early graft failure is a concern.
- Apoptosis (programmed cell death) is implicated in graft dysfunction.
- The role of mechanical stress in vein graft apoptosis is not fully understood.
Purpose of the Study:
- To investigate apoptosis in early-stage vein grafts.
- To determine the mechanisms by which mechanical stress induces apoptosis in vascular smooth muscle cells (SMCs).
Main Methods:
- Assessed apoptosis in mouse vein grafts using morphological changes and TUNEL staining.
- Applied cyclic strain to cultured mouse, rat, and human arterial SMCs.
- Measured p38 mitogen-activated protein kinase (MAPK) activity and utilized specific inhibitors and genetic manipulation (dominant-negative rac, MAPK phosphatase-1).
Main Results:
- Apoptosis was confirmed in vein grafts, peaking at 4 weeks post-surgery, particularly in artery-to-vein grafts.
- Cyclic strain induced time- and strength-dependent apoptosis in all tested SMC types.
- Mechanical stress activated p38 MAPK within 8 minutes; inhibition of p38 MAPK prevented apoptosis.
Conclusions:
- Apoptosis is an early event in vein graft remodeling.
- Mechanical stress-induced p38 MAPK activation is a key signaling pathway mediating apoptosis in vascular SMCs within vein grafts.
- Targeting the p38 MAPK pathway may offer therapeutic strategies to improve vein graft patency.