Biomedical subjects

Manuel Mayr

Publications and source records attributed to Manuel Mayr.

25 records · Page 2Linked to original sources

PubMed2003

Mechanical stretch-induced apoptosis in smooth muscle cells is mediated by beta1-integrin signaling pathways.

Recently we demonstrated that mechanical stress induces apoptosis of vascular smooth muscle cells in vitro and in vein grafts (Mayr et al. FASEB J. 2000;15:261-270). The current study was designed to investigate molecular mechanisms of mechanical stretch-induced apoptosis. Smooth muscle cells cultivated on silicone elastomer plates precoated with collagen I, elastin, laminin, or Pronectin were subjected to cyclic mechanical stretch. Interestingly, in response to mechanical stress, the number of apoptotic cells increased significantly in cells growing on collagen I-coated plates but not on other matrixes. We therefore thought that receptors mediating binding to collagen I, such as integrin beta1 containing receptors, might be involved in signaling pathways leading to stretch-induced apoptosis. On collagen plates, mechanical stress rapidly activated p38 MAPK that phosphorylated p53 in smooth muscle cells. Lack of functional Rac completely abrogated p38 MAPK-p53 activation as well as apoptosis. Furthermore, mechanical stress resulted in increases of both integrin beta1 protein expression and activity as identified by Western blotting and Shc immunoprecipitation assays. Treatment with a beta1-integrin-blocking antibody or integrin signaling inhibitor cytochalasin B but not growth factor receptor inhibitor suramin abrogated both stretch-induced phosphorylation of p38 MAPK and p53 expression. Akin to the inhibition of p38 MAPK-p53 signaling, pretreatment with a beta1-integrin-blocking antibody or cytochalasin B but not suramin inhibited stretch-induced apoptosis on collagen plates. These results suggest that mechanical stress-induced apoptosis in vascular smooth muscle cells is mediated by beta1-integrin-rac-p38-p53 signaling pathways.

Animals↗

PubMed2003

Increased risk of atherosclerosis is confined to CagA-positive Helicobacter pylori strains: prospective results from the Bruneck study.

BACKGROUND AND PURPOSE: Accumulating evidence indicates that a variety of infections contribute to the pathogenesis of atherosclerosis, but there is controversy concerning the impact of Helicobacter pylori infections in atherosclerosis. METHODS: We evaluated seropositivity to H pylori and to its cytotoxin-associated gene A (CagA) product in a large, prospective, population-based study (n=684). Intima-media thickness and atherosclerosis of carotid arteries were thoroughly assessed by high-resolution duplex scanning. RESULTS: In our study population, H pylori infections defined by seropositivity have no relationship with levels of classic cardiovascular risk factors or markers of systemic inflammation, except for elevated levels of immune reactions to mycobacterial heat shock protein 65. The latter showed a trend toward highest levels in those harboring virulent H pylori strains (P=0.08). Common carotid artery intima-media thickness-both absolute values and changes between 1995 and 2000-were significantly enhanced in subjects seropositive to CagA but not in those infected with CagA-negative H pylori strains. There was a clear dose-response relation between anti-CagA antibodies and both intima-media thickness and atherosclerosis risk. Notably, the risk of atherosclerosis associated with CagA seropositivity was amplified by elevated C-reactive protein levels. CONCLUSIONS: Infections with virulent CagA-bearing H pylori strains may contribute to the pathogenesis of early atherosclerosis by aggravating immune-inflammatory reactions.

Adult↗

PubMed2002

Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions.

Smooth muscle cell (SMC) accumulation in the inner layer of the vessel wall is a key event in the pathogenesis of atherosclerosis in vein grafts, but the origin of the cells in these lesions has yet to be shown. Herein, we use animal models of vein grafts in transgenic mice to clearly identify the sources of SMCs in atherosclerosis. Vena cava segments were isografted to carotid arteries between four types of transgenic mice, including SM-LacZ expressing beta-galactosidase (beta-gal) in vascular SMCs, SM-LacZ/apoE(-/-), ROSA26 expressing beta-gal in all tissues, and wild-type mice. beta-gal-positive cells were observed in neointimal and atherosclerotic lesions of all vein segments grafted between LacZ transgenic and wild-type mice. Double staining for beta-gal and cell nuclei revealed that about 40% of SMCs originated from hosts and 60% from the donor vessel. This was confirmed by double labeling of the Y-chromosome and alpha-actin in the lesions of sex-mismatched vein grafts. The possibility that bone marrow cells were the source of SMCs in grafts was eliminated by the absence of beta-gal staining in atherosclerotic lesions of chimeric mice. Furthermore, vein SMCs of SM-LacZ mice did not express beta-gal in situ, but did so when these cells appeared in atherosclerotic lesions in vivo, suggesting that hemodynamic forces may be crucial for SMC differentiation. Thus, we provide the first evidence of SMC origins in the atherosclerotic lesions of vein grafts, which will be essential for providing insight into new types of therapy for the disease. The full text of this article is available at http://www.circresaha.org.

Actins↗

PubMed2002

Smooth muscle cells in transplant atherosclerotic lesions are originated from recipients, but not bone marrow progenitor cells.

BACKGROUND: Smooth muscle cell (SMC) accumulation in the intima of vessels is a key event in the pathogenesis of transplant atherosclerosis. The traditional hypothesis that SMCs in the lesion are derived from the media of the donor vessel has been challenged by recent observations, but the cell origin is still not well established. METHODS AND RESULTS: Here, we use a simplified model of artery allografts in transgenic mice to clearly identify the source of SMCs in transplant atherosclerosis. Aortic segments donated by BALB/c mice allografted to ROSA26 (C57B/6) mice expressing beta-galactosidase (gal) in all tissues showed that neointimal cells derived exclusively from host cells. It was also demonstrated that SMCs of neointimal and atherosclerotic lesions in vessels allografted to mice expressing beta-gal only in SMCs (SM-LacZ) or to apoE-deficient/SM-LacZ mice originated from the recipient, and not donor vessels. Interestingly, bone marrow transplantation of SM-LacZ beta-gal-expressing cells into aortic allograft recipients revealed completely negative beta-gal staining of neointimal and atherosclerotic lesions. However, a population of beta-gal-positive cells in lesions of allografts was observed in chimeric mice with ROSA26 beta-gal-expressing marrow cells. When bone marrow cells from both ROSA26 and SM-LacZ mice were cultured and stimulated with platelet-derived growth factor-BB, alpha-actin and beta-gal double-positive cells were found, suggesting that bone marrow cells have an ability to differentiate into SMCs. CONCLUSIONS: Thus, we provide strong evidence that SMCs of neointimal and atherosclerotic lesions in allografts are derived from the recipients and that non-bone marrow-derived progenitor cells are a possible source of SMCs in atherosclerotic lesions.

Actins↗

PubMed2002

Mechanical stress-induced DNA damage and rac-p38MAPK signal pathways mediate p53-dependent apoptosis in vascular smooth muscle cells.

Recently, we demonstrated that biomechanical stress induces apoptosis of vascular smooth muscle cells (SMCs) (Mayr et al., FASEB J. 2000; 15:261-270). In this article we investigated the molecular mechanisms of mechanical stress-induced apoptosis. When SMCs were subjected to cyclic strain, tumor-suppressor p53 was activated as evidenced by gel mobility shift assays and Western blot analyses. p53 activation was largely attenuated if SMCs were pretreated with SB202190, a specific p38MAPK inhibitor, or were stably transfected with dominant negative rac, an upstream signal transducer of p38MAPK pathways. Kinase assays provided direct evidence that p38MAPKs phosphorylated p53 within 30 min of cyclic strain. Additionally, mechanical stress resulted in oxidative DNA damage as detected by the presence of 8-oxoguanine. Treatment with the antioxidant U-74389G abrogated p53 activation. p53 activation was followed by expression and mitochondrial translocation of the proapoptotic protein Bax. Likewise, mechanical stress resulted in up-regulation of anti-apoptotic Bcl-2 proteins, including Bcl-2 and Bcl-xL. However, a marked loss of mitochondrial membrane potential occurred in wild-type, but not in p53-/-, SMCs. The latter lost their ability to express Bax and showed no apoptosis in response to cyclic strain. Taken together, our data provide the first evidence that SMC apoptosis induced by mechanical stress is p53-dependent.

Animals↗

PubMed2002

Loss of p53 accelerates neointimal lesions of vein bypass grafts in mice.

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.

Actins↗

PubMed2002

Active and passive smoking, chronic infections, and the risk of carotid atherosclerosis: prospective results from the Bruneck Study.

BACKGROUND AND PURPOSE: Susceptibility of the vasculature to the injurious effects of smoking varies substantially, with some smokers developing severe premature atherosclerosis and others remaining free of advanced atheroma until high ages. The present study sought to estimate the contribution of chronic infections to the variability of atherosclerosis severity among smokers. METHODS: In the community-based Bruneck Study, 5-year changes in carotid atherosclerosis were assessed by high-resolution ultrasound. Early atherogenesis was defined by the development of nonstenotic plaques and advanced atherogenesis by the development/progression of vessel stenosis >40%. RESULTS: The risk of early atherogenesis strongly relied on lifetime smoking exposure and remained elevated long-term after cessation of smoking. Remarkably, current and ex-smokers faced an increased atherosclerosis risk only in the presence of chronic infections (odds ratios [95% CIs], 3.3 [1.8 to 6.2] and 3.4 [1.8 to 6.3]; P<0.001 each), whereas current, past, and nonsmokers without infections did not differ substantially in their estimated risk burden (odds ratios [95% CIs], 1.4 [0.8 to 2.4], 0.9 [0.6 to 1.6], and 1.0 [reference group]). In analogy to first-hand smoking, subjects exposed to environmental tobacco smoke were found to be vulnerable to the manifestation of chronic infection, and only those infected experienced a high atherosclerosis risk. The risk of advanced atherogenesis showed a dose-response relation with the number of daily cigarettes, returned to normal shortly after cessation of smoking, and emerged as independent of infectious illness. CONCLUSIONS: Our study provides the first epidemiological evidence that the proatherogenic effects of cigarette smoking are mediated in part by the chronic infections found in smokers. A better understanding of the vascular pathogenetic mechanisms of smoking may offer novel clues for disease prevention supplementary to the primary goal of achieving long-term abstinence.

Adult↗