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Barbara Messner,
Johann Kern,
Dominik Wiedemann,
Stefan Schwaiger,
Adrian Tü Rkcan,
Christian Ploner,
Alexander Trockenbacher,
Klaus Aumayr,
Nikolaos Bonaros,
Gü Nther Laufer,
Hermann Stuppner,
Gerold Untergasser, David Bernhard
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ABSTRACT: Background: Insufficient angiogenesis and arteriogenesis in cardiac tissue after myocardial infarction (MI) is a significant factor hampering the functional recovery of the heart. To overcome this problem we screened for compounds capable of stimulating angiogenesis, and herein investigate the most active molecule, 5-Methoxyleoligin (5ML), in detail.
PLoS ONE 03/2013; 8(3):e58342. · 4.09 Impact Factor
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ABSTRACT: Cigarette smoke is an aerosol that contains >4,000 chemicals, including nicotine, carbon monoxide, acrolein, and oxidant compounds. Exposure to cigarette smoke induces multiple pathological effects in the endothelium, several of which are the result of oxidative stress initiated by reactive oxygen species, reactive nitrogen species, and other oxidant constituents of cigarette smoke. Cigarette-smoke exposure interferes adversely with the control of all stages of plaque formation and development and pathological thrombus formation. The reactive oxygen species in cigarette smoke contribute to oxidative stress, upregulation of inflammatory cytokines, and endothelial dysfunction, by reducing the bioavailability of nitric oxide. Plaque formation and the development of vulnerable plaques also result from exposure to cigarette smoke via the enhancement of inflammatory processes and the activation of matrix metalloproteases. Moreover, exposure to cigarette smoke results in platelet activation, stimulation of the coagulation cascade, and impairment of anticoagulative fibrinolysis. Many cigarette-smoke-mediated prothrombotic changes are quickly reversible upon smoking cessation. Public health efforts should urgently promote our understanding of current cigarette-smoke-induced cardiovascular pathology to encourage individuals to reduce their exposure to cigarette smoke and, therefore, the detrimental consequences of associated atherothrombotic disease.
Nature Reviews Cardiology 02/2013; · 8.83 Impact Factor
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Barbara Messner,
Johann Kern,
Dominik Wiedemann,
Stefan Schwaiger,
Adrian Türkcan,
Christian Ploner,
Alexander Trockenbacher,
Klaus Aumayr,
Nikolaos Bonaros,
Günther Laufer,
Hermann Stuppner,
Gerold Untergasser, David Bernhard
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ABSTRACT: Insufficient angiogenesis and arteriogenesis in cardiac tissue after myocardial infarction (MI) is a significant factor hampering the functional recovery of the heart. To overcome this problem we screened for compounds capable of stimulating angiogenesis, and herein investigate the most active molecule, 5-Methoxyleoligin (5ML), in detail.
5ML potently stimulated endothelial tube formation, angiogenic sprouting, and angiogenesis in a chicken chorioallantoic membrane assay. Further, microarray- and knock down- based analyses revealed that 5ML induces angiogenesis by upregulation of CYP26B1. In an in vivo rat MI model 5ML potently increased the number of arterioles in the peri-infarction and infarction area, reduced myocardial muscle loss, and led to a significant increase in LV function (plus 21% 28 days after MI).
The present study shows that 5ML induces CYP26B1-dependent angiogenesis in vitro, and arteriogenesis in vivo. Whether or not CYP26B1 is relevant for in vivo arteriogenesis is not clear at the moment. Importantly, 5ML-induced arteriogenesis in vivo makes the compound even more interesting for a post MI therapy. 5ML may constitute the first low molecular weight compound leading to an improvement of myocardial function after MI.
PLoS ONE 01/2013; 8(3):e58342. · 4.09 Impact Factor
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ABSTRACT: Cadmium is a highly toxic, carcinogenic, and atherogenic element. A central principle in many Cd-induced pathophysiologies is the induction of cell death. In past studies Cd was shown to cause apoptosis, necrosis, programmed necrosis, or autophagy. This study was conducted to precisely define the end stage processes and outcome of Cd-induced cell death in endothelial cells (ECs). We show that Cd leads to acidification and permeabilization of lysosomes, followed by the release of active DNAse II from lysosomes. The absence of nuclear DNA due to DNAse II activity may have lead to misinterpretations of the type of cell death outcome in previous studies. Further, Cd-induced cell death is characterized by a massive release of lactate dehydrogenase (LDH), a gold standard marker for the occurrence of plasma membrane rupture i.e. necrosis. Importantly, lentivirus-based over-expression of the anti-apoptotic protein BCL-XL abrogates lysosomal rupture, DNA degradation and LDH release, clearly indicating that Cd induces a programmed form of cell death with a necrotic endpoint.
Toxicology Letters 06/2012; 212(3):268-75. · 3.23 Impact Factor
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ABSTRACT: Despite rapid progress in surgical techniques, there is still a significant lack of surgery-supportive pharmacological treatments. The aim of this study was to test the hypothesis that ursolic acid (UA) may prevent intimal hyperplasia of venous bypass grafts.
The hypothesis was tested by means of primary cell isolation and culture followed by real-time polymerase chain reaction, western blotting, fluorescence microscopy and fluorescence-activated cell sorting analyses, as well as an in vivo rat model for intimal hyperplasia of venous bypass grafts and immunohistochemistry and histochemistry.
The local application of UA significantly inhibited intimal hyperplasia in vivo (intimal thickness control: 25 µm, UA group: 18 µM-8 weeks after surgery). The UA treatment of grafts significantly resulted in reduced endothelial vascular cell adhesion molecule-1 (VCAM-1) expression, reduced infiltration of the grafts vessel wall by CD45-positive cells and increased smooth muscle cell (SMC) death. In in vitro condition, it could be shown that UA inhibits VCAM-1 expression downstream of NFκB and is likely to interfere with VCAM-1 protein synthesis in endothelial cells. Quantification of cell death in vascular smooth muscle cells treated with UA indicated that UA is a potent inducer of SMC apoptosis.
Our results suggest that UA-mediated inhibition of endothelial VCAM-1 expression reduces the infiltration of venous bypass grafts by CD45-positive cells and inhibits intimal hyperplasia. Apoptosis induction in SMCs may be another method in which UA reduces intimal thickening. UA may constitute a surgery-supportive pharmacon that reduces intimal hyperplasia of vein grafts.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 05/2012; 42(5):878-84. · 2.40 Impact Factor
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Stefan Blunder,
Barbara Messner,
Thomas Aschacher,
Iris Zeller,
Adrian Türkcan,
Dominik Wiedemann,
Martin Andreas,
Gert Blüschke,
Günther Laufer,
Thomas Schachner, David Bernhard
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ABSTRACT: Past studies on the pathogenesis of thoracic aortic aneurysms have, by concentrating on histological and total tissue analyses, revealed several disease-relevant processes. Despite these studies, there is still a significant lack in the understanding of aneurysmal cell biology today. Hence, it was the goal of this study to assess differences between aneurysmal and healthy aortic smooth muscle cells (SMCs) on a broad - screening-like - basis, allowing us to formulate new hypotheses on the role of SMCs in thoracic aneurysm formation.
After histological characterization of a total of 16 samples from healthy aortas and thoracic aortic aneurysms (TAA) of patients with bicuspid (BAV) and tricuspid (TAV) aortic valves, we isolated aortic SMCs and subjected them to cell biological and gene expression analyses. The data obtained indicate that aneurysmal SMCs exert reduced proliferation and migration rates compared to controls. BAV TAA SMCs have significantly shorter telomeres, whereas TAV TAA SMCs showed a reduced metabolic activity. In BAV TAA SMCs osteopontin (OPN) expression was significantly elevated, and TAV TAA SMCs showed decreased expression of tissue inhibitor of metalloproteinase 3 (TIMP3).
Our study provides evidence that TAA-associated aortic wall disintegration in BAV and TAV TAAs shows similarities, but also significant differences. BAV and TAV TAAs differ with regard to medial elastic fiber mass and the occurrence of fibroblasts, SMC telomere length, metabolism, and gene expression. This study may form the basis for future in-depth analyses on the relevance of these findings in the pathophysiology of BAV and TAV TAAs.
Atherosclerosis 11/2011; 220(2):355-61. · 3.79 Impact Factor
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Michael Knoflach,
Barbera Messner,
Ying H Shen,
Sandra Frotschnig,
Guanghui Liu,
Kristian Pfaller,
Xingli Wang,
Benjamin Matosevic,
Johann Willeit,
Stefan Kiechl,
Günther Laufer, David Bernhard
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ABSTRACT: Cadmium is a potential new risk factor for early atherosclerosis and cardiovascular diseases in humans, yet pathogenetic mechanisms are still a matter of debate.
In-depth histological analysis of 18 sections taken from 6 cadmium-fed ApoE-/- mice and 12 sections from 5 litter-mates not exposed to cadmium by light and scanning electron microscopy was performed. Cadmium-fed mice showed a marked increase in lesion load (plaque area) and severity as classified according to the American Heart Association vascular lesion grading. All inflammatory markers studied (CD68, CD3, CD25, vascular cell adhesion molecule 1 (VCAM-1), and heat shock protein 60 (Hsp60)) yielded a higher expression in cadmium-fed mice. Statistical difference was achieved for VCAM-1 and Hsp60 (P=0.03 and P=0.02). The shoulder region of atherosclerotic plaques in cadmium-fed mice showed a prominent retraction of endothelial cells on electron microscopy.
Our data indicate that cadmium exposure amplifies the development of vessel pathology in atherosclerosis susceptible ApoE-/- mice and suggests upregulation of VCAM-1 and Hsp60 and endothelial leakage as potential pathomechanisms.
Circulation Journal 07/2011; 75(10):2491-5. · 3.77 Impact Factor
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Kristina Duwensee,
Stefan Schwaiger,
Ivan Tancevski,
Kathrin Eller,
Miranda van Eck,
Patrick Markt,
Tobias Linder,
Ursula Stanzl,
Andreas Ritsch,
Josef R Patsch,
Daniela Schuster,
Hermann Stuppner, David Bernhard,
Philipp Eller
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ABSTRACT: Cholesteryl ester transfer protein (CETP) plays a central role in the metabolism of high-density lipoprotein particles. Therefore, we searched for new drugs that bind to CETP and modulate its activity.
A preliminary pharmacophore-based parallel screening approach indicated that leoligin, a major lignan of Edelweiss (Leontopodium alpinum Cass.), might bind to CETP. Therefore we incubated leoligin ex vivo at different concentrations with human (n=20) and rabbit plasma (n=3), and quantified the CETP activity by fluorimeter. Probucol served as positive control. Furthermore, we dosed CETP transgenic mice with leoligin and vehicle control by oral gavage for 7 days and measured subsequently the in vivo modulation of CETP activity (n=5 for each treatment group).
In vitro, leoligin significantly activated CETP in human plasma at 100 pM (p=0.023) and 1 nM (p=0.042), respectively, whereas leoligin concentrations of 1 mM inhibited CETP activity (p=0.012). The observed CETP activation was not species specific, as it was similar in magnitude for rabbit CETP. In vivo, there was also a higher CETP activity after oral dosage of CETP transgenic mice with leoligin (p=0.015). There was no short-term toxicity apparent in mice treated with leoligin.
CETP agonism by leoligin appears to be safe and effective, and may prove to be a useful modality to alter high-density lipoprotein metabolism.
Atherosclerosis 07/2011; 219(1):109-15. · 3.79 Impact Factor
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ABSTRACT: Heat shock protein 60 (HSP60), expressed on the surface of endothelial cells (ECs) stressed by e.g. oxidized LDL or mechanical shear, was shown to function as an auto-antigen and thus as a pro-atherosclerotic molecule. The aim of this study was to determine whether cigarette smoke chemicals can lead to the activation of the "HSP60 pathway." It was also our aim to elucidate the dynamics of HSP60 from gene expression to endothelial surface expression and secretion. Here we show for the first time that the exposure of human umbilical vein endothelial cells (HUVECs) to cigarette smoke extract (CSE) results in an up-regulation of HSP60 mRNA. Live cell imaging analysis of a HSP60-EYFP fusion protein construct transfected into ECs revealed that mitochondrial structures collapse in response to CSE exposure. As a result, HSP60 is released from the mitochondria, transported to the cell surface, and released into the cell culture supernatant. Analysis of HSP60 in the sera of healthy young individuals exposed to secondhand smoke revealed significantly elevated levels of HSP60. Cigarette smoking is one of the most relevant risk factors for atherosclerosis. Herein, we provide evidence that cigarette smoke may initiate atherosclerosis in the sense of the "auto-immune hypothesis of atherosclerosis."
Journal of Molecular and Cellular Cardiology 07/2011; 51(5):777-80. · 5.17 Impact Factor
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ABSTRACT: The plant derived triterpene ursolic acid (UA) has been intensively studied in the past; mainly as an anti-cancer compound and for its cardiovascular protective properties. Based on the controversy of reports suggesting anti-angiogenic and cytotoxic effects of UA on one side and cardiovascular and endothelial protective effects on the other side, we decided to assess UA effects on primary human endothelial cells in vitro and atherosclerotic plaque formation in vivo.
Our in vitro analyses clearly show that UA inhibits endothelial proliferation and is a potent inducer of endothelial cell death. UA causes DNA-damage, followed by the activation of a p53-, BAK-, and caspase-dependent cell-death pathway. Oral application of UA in APO E knockout mice potently stimulated atherosclerotic plaque formation in vivo, which was correlated with decreased serum levels of the athero-protective cytokine IL-5.
Due the potent endothelial cell death inducing activity of UA, a systemic application of UA in the treatment of cardiovascular diseases seems unfavourable. UA as an anti-angiogenesis, anti-cancer and - locally applied - cardiovascular drug may be helpful. The DNA damaging activity of UA may however constitute a serious problem.
Atherosclerosis 06/2011; 219(2):402-8. · 3.79 Impact Factor
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ABSTRACT: Consumption of cigarette smoke (CS) is a well-known risk factor for early atherosclerosis; yet, the underlying mechanisms of smoking-associated atherosclerosis are poorly understood. Based on the previous results indicating that CS-induced endothelial cell death neither shows typical features of apoptosis nor of necrosis, we investigated the role of autophagy in CS extract (CSE)-induced cell death of human umbilical vein endothelial cells (HUVECs).
Here, we demonstrate that overexpression of the classical apoptosis inhibitor BCL-XL had no protective effect on CSE-induced cell death, whereas the autophagy inhibitor 3-methyladenin and an shRNAi-mediated knockdown of the autophagy mediator ATG5 significantly delayed cell death. Our results indicate that CSE induces an excess accumulation of misfolded proteins in the endoplasmic reticulum (ER) and consequently the onset of the unfolded protein response. We provide evidence that the ER-resident kinase PERK is a major transducer of ER stress leading to phosphorylation of eIF2α and attenuation of protein synthesis. Finally, we show that prolonged ER stress in cells subjected to CS is followed by activation of an autophagic programme. CSE-induced autophagy is characterized by an increase in LC3 II/I ratio and activation ATG12. The autophagic signalling pathway via energy depletion and consequent activation AMP-activated protein kinase could be excluded.
Our results confirm and extend previous findings reporting on the induction of autophagy by CSE in the lung. We show that protein damage caused by CSE activates autophagy, ultimately resulting in necrotic death of HUVECs. Via this mechanism, cigarette smoking may contribute to the deterioration of vascular endothelial function and the initiation of atherosclerosis.
Cardiovascular research 06/2011; 92(1):141-8. · 5.80 Impact Factor
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ABSTRACT: Indian hemp is used since thousands of years as herbal drug. We found that a single dose of cannabis resin was equally active as Δ9-tetrahydrocannabinol (THC) enhancing severity and duration of symptoms in vaccinia virus infected mice. Cowpox virus did not cause symptomatic disease, but some reduction of specific antibody production was observed in drug treated animals. In vitro cannabis was superior to THC alone at inhibiting mitogen stimulated proliferation of human and mouse spleen cells and peripheral blood mononuclear cells. Also resin sub-fractions other than THC, cannabidiol and cannabinol, recovered also from cigarette smoke, were found inhibitory, suggesting additional involvement of constituents other than psychoactive THC. The immunoregulatory effects must be differentiated from apoptotic effects on spleen cells and lymphocytic mouse cell lines, which were observed with resin and THC but not with cannabidiol or cannabinol. A significant contribution of cytotoxic effects seems unlikely as drug treated lymphocytes were still capable of producing cytokines after T-cell receptor-specific stimulation. Considering a recent case of unusually severe cowpox virus infection in a young drug taker these data confirm a risk of "soft drugs" for acquiring poxvirus infection or enhancing side effects of the smallpox vaccine and perhaps also other live vaccines.
Immunobiology 11/2010; 216(6):670-7. · 3.20 Impact Factor
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ABSTRACT: The performed investigations aimed on the identification of the anti-inflammatory principal of extracts of leaves of Sambucus ebulus L. (dwarf elder) in order to rationalize the traditional use of this plant for the treatment of chronically inflammatory diseases.
Dwarf elder leaf extract was subjected to activity guided fractionation using inhibition of TNFα induced expression of vascular cell adhesion molecule 1 (VCAM-1) on the surface of human umbilical vein endothelial cells (HUVECs) as monitoring tool (positive control: parthenolide 10μM, VCAM-1 expression (% of control): 5.35±0.38%).
Bio-guided isolation resulted in identification of ursolic acid as anti-inflammatory principal. Besides its inhibitory effects against TNFα induced expression of VCAM-1 (IC(50) 6.25 μM), ursolic acid inhibits also TNFα induced expression of ICAM-1 (IC(50) value between 3.13 and 6.25 μM) (positive control: parthenolide 10 μM, ICAM-1 expression (% of control): 38.89±16.6%). Toxic effects of ursolic acid on HUVECs can be drastically reduced using an enriched extract instead of the pure compound.
Our findings suggest an additional mechanism of the anti-inflammatory activity of ursolic acid by demonstrating its ability to inhibit TNFα-stimulated expression of VCAM-1 and ICAM-1 and support the traditional use of extracts and preparations of Sambucus ebulus L., rich in ursolic acid, for the treatment of chronically inflammatory processes.
Journal of ethnopharmacology 10/2010; 133(2):704-9. · 2.32 Impact Factor
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ABSTRACT: The transition metal cadmium (Cd) is an environmental pollutant which damages the kidneys. Chronic Cd exposure may induce renal fibrosis and/or cancer, but the signaling pathways involved are not understood. The Wnt pathway is a key signaling cascade responsible for renal development, fibrosis and cancer. Hence the effect of chronic in vivo Cd exposure (100 mg/l drinking water for 12 weeks) on transcriptional activation of the Wnt pathway and markers of epithelial-to-mesenchymal transition (EMT) was investigated in mouse kidneys. Cd exposure increased kidney Cd content from 0.023+/-0.001 microg/g to 61+/-7 microg/g wet weight (means+/-S.D. of 6-7 animals). This was accompanied by increased expression of Wnt ligands (Wnt3a/6/7a/7b/9a/9b/10a/11), as determined by RT-PCR. The Wnt receptors Frizzled (Fz1/2/4,5,7-10) were also upregulated, as were the co-receptors low-density lipoprotein receptor-related proteins 5/6. Immunoblots with Wnt10a and Fz7 antibodies also revealed increased protein expression induced by Cd exposure. In contrast, Wnt antagonists were largely unaffected. Upregulation of Wnt signaling components induced by Cd was corroborated by increased expression of Wnt target genes, i.e. cell proliferation and survival genes c-Myc, cyclin D1 and the multidrug transporter P-glycoprotein Abcb1b, which promote malignancy. Lastly the EMT markers Twist, fibronectin and collagen I, but not alpha-smooth muscle actin, were also upregulated, suggesting that Cd-induced changes of renal epithelial tissue characteristics towards fibrosis and cancer may be mediated by Wnt signaling.
Toxicology Letters 09/2010; 198(1):69-76. · 3.23 Impact Factor
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Iris Zeller,
Michael Knoflach,
Andreas Seubert,
Simone B Kreutmayer,
Marlies E Stelzmüller,
Evelyn Wallnoefer,
Stefan Blunder,
Sandra Frotschnig,
Barbara Messner,
Johann Willeit,
Paul Debbage,
Georg Wick,
Stefan Kiechl,
Günther Laufer, David Bernhard
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ABSTRACT: To validate the hypothesis that the toxic heavy metal lead (Pb) may be linked to cardiovascular diseases via the initiation of atherosclerosis, in vivo and in vitro studies were conducted.
During the human study part of this project, serum Pb levels of healthy young women were correlated to carotid intima-media thickness. Multivariate logistic regression analyses showed that increased serum Pb levels were significantly associated with an increased intima-media thickness (P=0.01; odds ratio per SD unit, 1.6 [95% CI, 1.1 to 2.4]). In vitro, Pb induced an increase in interleukin 8 production and secretion by vascular endothelial cells. Nuclear factor erythroid 2-related factor-2 is the crucial transcription factor involved in Pb-induced upregulation of interleukin 8. Endothelial cell-secreted interleukin 8 triggered intimal invasion of smooth muscle cells and enhanced intimal thickening in an arterial organ culture model. This phenomenon was further enhanced by Pb-increased elastin synthesis of smooth muscle cells.
Our data support the hypothesis that Pb is a novel, independent, and significant risk factor for intimal hyperplasia.
Arteriosclerosis Thrombosis and Vascular Biology 09/2010; 30(9):1733-40. · 6.37 Impact Factor
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ABSTRACT: Today cardiovascular diseases (CVDs) are the killer number one world wide. In 2004 an estimated 17.1 million people died due to CVDs and this number will further increase to an estimated 23.6 million by 2030. Importantly, currently known risk factors, like hypertension, and hypercholesterolemia, can only be made responsible for about 50-75% of all CVDs, highlighting the urgent need to search for and define new CVD risk factors. Cadmium (Cd) was shown to have the potential to serve as one such novel risk factor, as it was demonstrated-in vitro, in animal studies, and in human studies-that Cd causes atherosclerosis (the basis of most CVDs). Herein, we discuss the molecular and cellular biological effects of Cd in the cardiovascular system; we present concepts on the pathophysiology of Cd-caused atherosclerosis, and provide data that indicate an epidemiological relevance of Cd as a risk factor for CVDs.
Biology of Metals 03/2010; 23(5):811-22. · 3.17 Impact Factor
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ABSTRACT: Due to the increase in average life expectancy and the higher incidence of cardiovascular disease with advancing age, more elderly patients present for cardiac surgery nowadays. Advances in pre- and postoperative care mean that more elderly patients can be operated on safely and with a satisfactory outcome. Currently, coronary artery bypass surgery, aortic and mitral valve surgery and surgery of the ascending aorta are performed in elderly patients.
In this review, we summarize the outcome of elderly patients undergoing various cardiac surgical procedures and give future perspectives for the treatment of elderly patients with cardiac surgery.
A PubMed search for the period from 1980 to February 2009 was conducted with the following key words: 'elderly patient', 'cardiac surgery', 'CABG aortic surgery', 'mitral valve surgery' and 'endocarditis'. Additional information concerning population demographics was obtained from the World Health Organization homepage.
More and more cardiac surgical procedures are offered to elderly patients. The short- and long-term survival rates of elderly patients are comparable to those of younger patients. Nevertheless, the risk for these patients is only acceptable in the absence of comorbidities. In particular, renal dysfunction, cerebrovascular disease and a poor clinical state are associated with a worse outcome in elderly patients.
The data available show that most cardiac surgical procedures can be performed in elderly patients with a satisfactory outcome. Careful patient selection, flawless surgery, meticulous hemostasis, perfect anesthesia and myoacardial protection are basic requirements for the success of cardiac surgery in elderly patients.
Gerontology 10/2009; 56(3):241-9. · 2.78 Impact Factor
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Barbara Messner,
Michael Knoflach,
Andreas Seubert,
Andreas Ritsch,
Kristian Pfaller,
Blair Henderson,
Ying H Shen,
Iris Zeller,
Johann Willeit,
Günther Laufer,
Georg Wick,
Stefan Kiechl, David Bernhard
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ABSTRACT: Although cadmium (Cd) is an important and common environmental pollutant and has been linked to cardiovascular diseases, little is known about its effects in initial stages of atherosclerosis.
In the 195 young healthy women of the Atherosclerosis Risk Factors in Female Youngsters (ARFY) study, cadmium (Cd) level was independently associated with early atherosclerotic vessel wall thickening (intima-media thickness exceeding the 90th percentile of the distribution; multivariable OR 1.6[1.1.-2.3], P=0.016). In line, Cd-fed ApoE knockout mice yielded a significantly increased aortic plaque surface compared to controls (9.5 versus 26.0 mm(2), P<0.004). In vitro results indicate that physiological doses of Cd increase vascular endothelial permeability up to 6-fold by (1) inhibition of endothelial cell proliferation, and (2) induction of a caspase-independent but Bcl-xL-inhibitable form of cell death more than 72 hours after Cd addition. Both phenomena are preceded by Cd-induced DNA strand breaks and a cellular DNA damage response. Zinc showed a potent protective effect against deleterious effects of Cd both in the in vitro and human studies.
Our research suggests Cd has promoting effects on early human and murine atherosclerosis, which were partly offset by high Zn concentrations.
Arteriosclerosis Thrombosis and Vascular Biology 07/2009; 29(9):1392-8. · 6.37 Impact Factor
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Ute Reisinger,
Stefan Schwaiger,
Iris Zeller,
Barbara Messner,
Robert Stigler,
Dominik Wiedemann,
Tobias Mayr,
Christoph Seger,
Thomas Schachner,
Verena M Dirsch,
Angelika M Vollmar,
Johannes O Bonatti,
Hermann Stuppner,
Günther Laufer, David Bernhard
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ABSTRACT: Despite the lower patency of venous compared with arterial coronary artery bypass grafts, approximately 50% of grafts used are saphenous vein conduits because of their easier accessibility. In a search for ways to increase venous graft patency, we applied the results of a previous pharmacological study screening for non-toxic compounds that inhibit intimal hyperplasia of saphenous vein conduits in organ cultures. Here we analyse the effects and mechanism of action of leoligin [(2S,3R,4R)-4-(3,4-dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)tetrahydrofuran-3-yl]methyl (2Z)-2-methylbut-2-enoat, the major lignan from Edelweiss (Leontopodium alpinum Cass.).
We found that leoligin potently inhibits vascular smooth muscle cell (SMC) proliferation by inducing cell cycle arrest in the G1-phase. Leoligin induced cell death neither in SMCs nor, more importantly, in endothelial cells. In a human saphenous vein organ culture model for graft disease, leoligin potently inhibited intimal hyperplasia, and even reversed graft disease in pre-damaged vessels. Furthermore, in an in vivo mouse model for venous bypass graft disease, leoligin potently inhibited intimal hyperplasia.
Our data suggest that leoligin might represent a novel non-toxic, non-thrombogenic, endothelial integrity preserving candidate drug for the treatment of vein graft disease.
Cardiovascular research 03/2009; 82(3):542-9. · 5.80 Impact Factor
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Michael Knoflach,
Stefan Kiechl,
Daniela Penz,
Alexandra Zangerle,
Christoph Schmidauer,
Andrea Rossmann,
Mahavir Shingh,
Ralf Spallek,
Andrea Griesmacher, David Bernhard,
Peter Robatscher,
Waltraud Buchberger,
Walter Draxl,
Johann Willeit,
Georg Wick
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ABSTRACT: Little research has been conducted into risk factors of atherosclerosis development in young women.
This cross-sectional study enrolled 205 18- to 22-year-old female students from the Educational Centre for Allied Health Professions. A broad array of risk conditions and lifestyle behaviors was carefully assessed. Intima media thickness (IMT) was used as a well-established surrogate for atherosclerosis and a predictor of vascular risk. High IMT was defined as levels exceeding the 90th percentile in the common and/or internal carotid arteries.
In multivariable logistic regression analysis, systolic blood pressure, family history for hypertension, lipoprotein(a), homocysteine, T-cell immune reaction against human heat shock protein 60, and exposure to environmental tobacco smoke and exhaust gases emerged as independent predictors of high IMT. Obesity, metabolic syndrome, and classical risk factors other than high blood pressure were rare and unrelated to IMT. Findings were similar once focusing on IMT as a continuous variable.
In female youngsters displaying initiating stages of vascular pathology, blood pressure level and numerous nontraditional risk conditions showed a significant relation to high IMT. Our study indicates that (auto)immune processes, high lipoprotein(a), and environmental exposure to tobacco smoke and traffic exhaust may play a role in early atherogenesis.
Stroke 03/2009; 40(4):1063-9. · 5.73 Impact Factor
