Loss of p53 Accelerates Neointimal Lesions of Vein Bypass Grafts in Mice

Abstract

The transcription factor p53 is essentially involved in regulation of cell death and proliferation. Recently, we have established a mouse model for vein graft arteriosclerosis by grafting autologous jugular veins or vena cava to carotid arteries. Using this model, we studied the role of p53 in the development of vein graft arteriosclerosis in p53(-/-) mice. Four weeks after grafting, neointimal hyperplasia of vein grafts in p53(-/-) mice was increased 2-fold compared with that of wild-type controls. Cell component analysis revealed that neointimal lesions in p53(-/-) mice consisted mainly of alpha-actin positive smooth muscle cells (SMCs), whereas the majority of cells in wild-type mice were MAC-1 (CD11b/18)-positive at 4 weeks. Importantly, SMC apoptosis as determined by TUNEL assay was significantly reduced in p53(-/-) vein grafts. TUNEL positive cells in wild-type vein grafts markedly increased from 0.5% to 6.4% of total cells 4 weeks postoperatively, but remained virtually unchanged in p53(-/-) grafts (0.8%). Immunofluorescence analysis revealed that increased p53 expression in neointimal SMCs of wild-type, but not p53(-/-), mice coincided with oxidative DNA damage in vein grafts. Interestingly, SMCs of p53(-/-) mice showed increased apoptosis in response to TNFalpha and decreased apoptosis in response to sodium nitroprusside. Additionally, p53-deficient SMCs showed a higher rate of proliferation and migration and expressed higher levels of matrix metalloproteinases. Thus, p53 deficiency accelerates neointima formation by facilitating SMC proliferation as well as abrogating cell apoptosis.

Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice

“…Because of suddenly elevated stretch stress to the vein graft, the majority of endothelial cells and SMCs in the vessel wall underwent apoptosis or necrosis (11,(33)(34)(35), suggesting a role for the remaining adventitial cells in the neointimal formation. Direct application of Sca-1 + cells to untreated vein grafts resulted in a lower number of transferred cells migrating to the neointima (data not shown).…”

“…The procedure used for immunofluorescent staining was similar to that described previously (35). Briefly, cell smears, frozen sections, and cultured cells were labeled with rat mAb's against Sca-1, hematopoietic lineages (Lin, including CD34, CD45, CD20, CD45RO, CD8, and TER-199), c-kit, CD31, CD34 (Abcam Ltd.), and MAC-1 (CD11a/18b), or a rabbit anti-vWF antibody (PharMingen), and visualized with swine antirabbit Ig or rabbit anti-rat Ig conjugated with FITC (Dakopatts) or Cy3.…”

Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by β 1 -Integrin Signaling Pathways

“…p53 is an essential element of this pathway, since lack of p53 prevented stretch-induced apoptosis. 12 The fact that both apoptosis and expression of 53 depend on ECM (the involvement of a different set of integrins) and that it can be blocked by cytochalasin B treatment and an integrin-␤ 1 -blocking antibody but not suramin strongly suggests that integrins represent important mechanosensors. By contrast, suramin blocks growth factor receptor-ERK pathways and proliferation of SMCs.…”

“…Based on our previous observations, 11,12 we wondered whether p38 MAPK and p53 are also essential parts of the signaling pathway leading to mechanical stress-induced SMC apoptosis on a collagen I matrix. Both stretch-induced phosphorylation of p38 MAPK and expression of p53 protein were induced in stretched SMCs on a collagen I matrix ( Figure 2A).…”

Coronary vein graft disease: Pathogenesis and prevention

“…In animal models, locally delivered gene therapy has prevented intimal hyperplasia in models of arterial balloon injury and venous grafts placed in arterial circulation (46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56) (Table 2). …”