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Biomedical subjects

F Mach

Publications and source records attributed to F Mach.

At least 19 recordsLinked to original sources
PubMed2006

[Erectile dysfunction: a potential useful marker for cardiovascular disease].

Erectile dysfunction is defined as the inability to achieve and/or maintain an erection sufficient to permit satisfactory sexual intercourse. Most cases of erectile dysfunction have a vascular etiology and, in patients with known cardiovascular disease, the degree of erectile dysfunction correlates with severity of that disease. In addition, cardiovascular disease and erectile dysfunction share the same risk factors for atherosclerosis and have a common pathophysiology (endothelial dysfunction); thus, erectile dysfunction appears as an early and sentinel symptom in patients with occult vascular disease, of the coronary or carotid arteries.

Biomarkers↗
PubMed2006

Leukocyte recruitment in atherosclerosis: potential targets for therapeutic approaches?

Atherosclerosis is a complex inflammatory disease involving cellular migration and interaction. Vascular injury in response to different cardiovascular risk factors enhances endothelial dysfunction, which in turn promotes the expression of inflammatory markers and transendothelial leukocyte migration. Recruitment of leukocytes from the blood stream into the vessel intima is a crucial step for the development of the disease. Recent findings have highlighted the role of chemokines, chemokine receptors, adhesion molecules, and gap junctions in this process by acting as chemoattractant, adhesive, or intercellular communication molecules. In this short review, we summarize new data concerning the different steps from leukocyte arrest to transendothelial migration and discuss potential new therapeutic approaches concerning these processes.

Animals↗
PubMed2005

[The contribution of molecular genetics to clinical cardiology: the example of hypertrophic cardiomyopathy].

Recent advances in molecular genetics have resulted in the identification of pathogenic mutations in a number of genes which cause hypertrophic cardiomyopathy (HCM). In order to integrate this increasing genetic knowledge of HCM into the cardiology clinic, we offer all patients and their families diagnosis and genetic counselling based on these current data. In addition, within the framework of a multidisciplinary project between the Divisions of Medical Genetics, Cardiology and Pediatric Cardiology of the University Hospitals of Geneva, we have developed a resequencing array enabling rapid molecular diagnosis of HCM. Data from this study will enhance our understanding of the aetiology of HCM, and improve our knowledge of genotype-phenotype correlations. This information will enable us to develop new therapeutic and preventive concepts, with the aim of tailoring therapies to the specific genetic variant of each patient and its family.

Cardiomyopathy, Hypertrophic↗
PubMed2005

Inflammation is a crucial feature of atherosclerosis and a potential target to reduce cardiovascular events.

Contrary to popular opinion, atherosclerosis is not a disease unique to modern civilization. In fact, atherosclerotic lesions have been found in the arteries of mummies dating back to 1,500 B.C., and yet our understanding of this complex process is still evolving. A fusion of basic science advances and clinical research findings has radically altered our traditional concepts about the pathogenesis and treatment of the clinical complications of atherosclerosis. Most physicians previously regarded the artery as a being merely a blood conduit that became encrusted with lipid detritus as part of the aging process. Modern-day treatment of atherosclerosis has arisen primarily from an understanding of the epidemiology of the disease rather than its pathophysiology, in that risk factors have traditionally been targeted. Our concepts of atherogenesis have evolved from vague ideas of inevitable degeneration to a much better defined scenario of molecular and cellular events. As we enhance our understanding of its fundamental mechanism, we can begin to approach atherogenesis as a modifiable rather than ineluctable process. Indeed, as we recognize now that inflammation plays a pivotal role in the process of atherosclerosis, it is noteworthy to evaluate the effect of modern therapies on this facet of the disease.

Animals↗
PubMed2005

Not all statins interfere with clopidogrel during antiplatelet therapy.

BACKGROUND: Clopidogrel and statins are frequently coadministered in patients with ischemic heart diseases. Recent reports suggested that clopidogrel's effectiveness in inhibiting adenosine diphosphate (ADP)-induced platelets aggregation is attenuated by co-administration of certain statins. The objective of the present study was to define which statin might interfere with the antiaggregation property of clopidogrel. METHODS: We designed a pharmacokinetic study and tested ex vivo platelet function on 21 healthy volunteers who received clopidogrel and all currently commercially available statins: rosuvastatin [10 mg o.d.], simvastatin [20 mg o.d.], fluvastatin [80 mg o.d.], pravastatin [40 mg o.d.], and atorvastatin [20 mg o.d.]. Each statin was administered for 7 days followed by 1 week of wash-out period with clopidogrel treatment alone. Detection of the statins in the plasma was performed on all blood samples, using HPLC analytical method. RESULTS: All individuals, except one, were responders to clopidogrel with inhibition of ex vivo ADP induced platelet aggregation. All statins, except pravastatin, were detectable in the plasma at the end of each treatment period in all patients, and no statin was detectable after any of the wash-out periods. Clopidogrel was significantly less efficient to prevent platelet aggregation when coadministrated with simvastatin or fluvastatin. No difference was observed in clopidogrel efficacy when coadministered with rosuvastatin, pravastatin or atorvastatin. CONCLUSIONS: This is the first study investigating clopidogrel-statin interactions on ex vivo platelet function with all commercially available statins and which were administered to the same individuals. It demonstrates in healthy volunteers that at the doses used in this study, simvastatin and fluvastatin, but not atorvastatin, pravastatin or rosuvastatin interfere with the anti-aggregation effect of clopidogrel.

Adult↗
PubMed2005

Pleiotropic effects of statins in atherosclerosis: role on endothelial function, inflammation and immunomodulation.

Atherosclerosis and its complications still represent the major cause of death in developed countries. Statins have been described as the most potent class of drugs to reduce serum cholesterol levels. The effectiveness and rapidity of statin-induced decreases in coronary events led to the speculation that statins possess also cholesterol-independent effects. By the inhibition of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme crucial to cholesterol synthesis, statins reduce not only cholesterol but also non steroidal isoprenoid intermediates production. Since these isoprenoids, such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate, regulate the small signaling proteins, Ras and Rho, inhibition of these prenylated proteins by statins might account for their non-lipid-related effects. In this review, we describe the numerous beneficial pleiotropic effects of statins that could modulate atherogenesis.

Arteriosclerosis↗
PubMed2003

Effects of statins on adhesion molecule expression in endothelial cells.

BACKGROUND: Inhibitors of HMG-CoA reductase are widely used to prevent atherosclerosis progression. The expression of adhesion molecules on activated endothelial cells (EC) is an important step in the initiation and progression of atherosclerosis. OBJECTIVES: We investigated whether adhesion molecule expression on activated EC is influenced by simvastatin, fluvastatin and pravastatin and, if so, by which mechanisms. METHODS: Human EC from umbilical veins or saphenous veins were pretreated overnight with statins with or without mevalonate, and also for simvastatin or fluvastatin with the isoprenoid intermediates, farnesyl pyrophosphate (FPP), or geranylgeranyl pyrophosphate (GGPP). After 4-6 h activation with tumor necrosis factor (TNF)-alpha or lipopolysaccharide (LPS), surface adhesion molecule expression was evaluated by ELISA and by flow cytometry. The same experiments were performed with selective inhibitors of geranylgeranyltransferase (GGTI-286) and farnesyltransferase (FTI-277). RESULTS: Pretreatment with simvastatin, fluvastatin or pravastatin potentiated the TNF-alpha and LPS-induced expression of E-selectin and VCAM-1, and mevalonate reversed the potentiating effect of these statins. GGPP also reversed the potentiating effect of simvastatin or fluvastatin on adhesion molecule expression, while FPP only partially reversed this effect. Furthermore, GGTI-286, but not FTI-277, mimicked the effect of simvastatin by increasing the TNF-alpha-mediated overexpression of E-selectin. CONCLUSIONS: Statins increase E-selectin- and VCAM-1-induced expression on vascular endothelial cells stimulated with TNF-alpha or LPS. The inhibition of geranylgeranylated proteins could contribute to this effect.

Cell Adhesion Molecules↗
PubMed2002

Statins: the new aspirin?

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been described as the principal and the most effective class of drug to reduce serum cholesterol levels. Statin therapies have been shown to reduce cardiovascular events, including myocardial infarction, stroke, and death, significantly, by altering vascular atherosclerosis development in patients with or without coronary artery disease symptoms. Extensive use of statins has led to the increase of some undesirable effects that are heavily counterbalanced by the benefits. Indeed, pleiotropic effects extend far beyond cholesterol reduction and involve non-lipid-related mechanisms that modify endothelial functions, immunoinflammatory responses, smooth muscle cell activation, proliferation and migration, atherosclerotic plaque stability, and thrombus formation. In this review, we describe in detail the targets and mechanisms of action of statins.

Adjuvants, Immunologic↗
PubMed2001

The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells.

HMG-CoA reductase inhibitors, or statins, are lipid-lowering agents that have been shown to effectively decrease severe rejection periods and development of transplant coronary artery disease after heart transplantation. Precise regulation of major histocompatibility complex class II (MHC class II) gene expression plays a pivotal role in control of the immune response after transplantation. The aim of this study was to evaluate the potential role of HMG-CoA reductase inhibitors in regulating the immune response. We have examined the effects of simvastatin on MHC class II expression in primary human endothelial cells. Using RNAse protection assay and flow cytometry, we observed that simvastatin dose-dependently reduced interferon-gamma (IFN-gamma) induced MHC class II expression (mRNA and protein). In contrast, simvastatin did not affect the expression of MHC class I, pointing to specific actions in the MHC class II signalling cascade. The transcriptional coactivator CIITA is the general regulator of both constitutive and inducible MHC class II expression. After stimulation with IFN-gamma, the CIITA gene is selectively activated via one (promotor IV) of its four promoters. Interestingly, mRNA levels of CIITA were decreased after treatment with simvastatin. In addition, using transient transfections of promoter-reporter constructs we observed that the activity of CIITA promoter IV was decreased by simvastatin. In conclusion, simvastatin selectively decreases IFN-gamma-induced MHC class II expression in human primary endothelial cells through actions on the CIITA promoter IV. Thus, the beneficial effects of statins reported after heart transplantation may result from this immunosuppressive action, suggesting possible therapeutic use for other immunological disorders as well.

Cells, Cultured↗
PubMed2001

Elevation of creatine kinase in acute severe asthma is not of cardiac origin.

OBJECTIVE: To study prospectively if, when plasma creatine kinase (CK) and plasma myoglobin are elevated, the origin of these abnormalities is cardiac or not, by measuring cardio-specific troponin T (cTT). METHOD: Fifteen patients with acute severe bronchial asthma (ASBA) were prospectively studied in the intensive care unit (ICU) with continuous electrocardiograph (ECG). Plasma CK, CK-MB, myoglobin and cTT were measured at 0, 4, 8, 12, 16 and 20 h in the ICU. RESULTS: Five out of 15 ASBA patients had elevated CK, four of them presenting with an increase in CK-MB. Plasma cTT was normal in every patient, including those with CK and/or myoglobin elevation. At admission to the ICU, myoglobin and CK were positively correlated (r = 0.760; p < 0.001). No patient was intubated. There was no difference in clinical signs or symptoms, medical history, laboratory values or ECG in patients with or without CK elevation. CONCLUSION: Patients admitted to an ICU for ASBA may present with an elevation of plasma CK, CK-MB and myoglobin not related to any heart injury. CK and CK-MB are not good markers of myocardial injury in ASBA patients due to the multitude of potential confounders. Therefore, troponin should be measured instead.

Acute Disease↗
PubMed2001

The role of chemokines in atherosclerosis.

Recruitment of mononuclear leukocytes and the migration, growth, and activation of the multiple cell types within atherosclerotic lesions are critical features of the chronic inflammatory and fibroproliferative response central to atherosclerosis. Attraction of leukocyte to tissues is controlled by chemokines, whose presence is well documented in atherosclerotic lesions. Studies using knockout and transgenic murine models have demonstrated that chemokine receptor/ligand interactions are of crucial importance in the development of atherosclerosis. Beyond their chemotactic effect on mononuclear leukocytes, chemokines may also interfere with smooth muscle cell migration and growth, as well as platelet activation and other well-defined features of the atherosclerotic process. There is no doubt that the identification of chemokines as important vascular signals has provided insights into our understanding of basic cellular and molecular mechanism of atherosclerosis. Thus, there is evidence that chemokine receptor/ligands could be identified as potential new targets for therapeutic intervention to prevent or control atherosclerosis in the near future.

Animals↗
PubMed2001

Cd40 ligand-deficient mice are protected against cerulein-induced acute pancreatitis and pancreatitis-associated lung injury.

BACKGROUND AND AIMS: The interactions between inflammatory cells and their mediators play important roles in many inflammatory processes, but their importance during acute experimental pancreatitis and pancreatitis-associated lung injury is unclear. To address the role of the interaction between CD40 and its ligand CD40L, molecules that mediate major immunoregulatory functions, pancreatitis was induced by administering supramaximal doses of cerulein in mice that do not express CD40L. METHODS: The severity of pancreatitis was measured by serum amylase activity, pancreatic edema, acinar cell necrosis, and pancreas myeloperoxidase activity (an indicator of neutrophil infiltration). Lung injury was quantitated by evaluating lung microvascular permeability and lung myeloperoxidase activity. RESULTS: In pancreatic tissue from control mice and cerulein-treated mice, the expression of both CD40 and CD40L was detected. Immunohistochemical analysis performed in isolated acini from wild-type pancreata showed that both CD40 and CD40L were expressed on the acinar cell surface. Interestingly, pancreatitis and pancreatitis-associated lung injury were markedly decreased in mice deficient in CD40L compared with wild-types. CONCLUSIONS: These observations indicate that CD40L plays an important proinflammatory role in pancreatitis and pancreatitis-associated lung injury.

Acute Disease↗
PubMed2000

Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis.

Although interruption of CD40-CD40L interactions via their respective mAbs yields prolonged allograft survival, the relative importance of CD40 or CD40L on donor or host cells remains unknown. Moreover, it is uncertain whether any allospecific tolerance occurring with CD40-CD40L blockade will also prevent allograft arteriopathy, the major long-term limitation to transplantation. Therefore, we performed cardiac transplantations using CD40L-deficient (CD40L-/-) mice to investigate the mechanisms underlying prolonged allograft survival. Without immunosuppression, wild-type (WT) hosts rejected allo-mismatched WT or CD40L-/- heart allografts within 2 wk. Conversely, allografts in CD40L-/- hosts beat vigorously for 12 wk. Anti-CD40 treatment did not induce graft failure in CD40L-/- recipients. Although graft-infiltrating cells were reduced approximately 50% in CD40L-/- hosts, the relative percentages of macrophages and T cell subsets were comparable to WT. IFN-gamma, TNF-alpha, and IL-10 were diminished commensurate with the reduced cellular infiltrate; IL-4 was not detected. CD40L-/- recipients did not develop IgG alloantibodies and showed diminished B7 and CD28 expression on subsets of graft-infiltrating cells. CD40L-/- transplant recipients developed allospecific tolerance to the donor haplotype; second set donor skin grafts engrafted well, whereas third-party skin grafts were vigorously rejected. By MLR, splenocytes from CD40L-/- allograft recipients also demonstrated allo-specific hyporesponsiveness. Nevertheless, allografts in CD40L-/- hosts developed significant graft arteriosclerosis by 8-12 wk posttransplant. Therefore, we propose that early alloresponses, without CD40-CD40L costimulation, induce allospecific tolerance but may trigger allo-independent mechanisms that ultimately result in graft vasculopathy.

Animals↗
PubMed2000

Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice.

Interruption of inflammatory pathways may provide a novel approach to the therapy of atherosclerosis. Recently, we and others have implicated the immune mediator dyad CD40/CD40L (CD40 ligand), which is expressed on endothelial and smooth muscle cells, macrophages, and T lymphocytes within human atherosclerotic lesions, in aspects of atherogenesis and the acute coronary syndromes, including regulation of matrix metalloproteinases, procoagulant activity, cytokines, etc. In vivo, interruption of CD40 signaling reduced the initiation and early phases of atheroma formation in hypercholesterolemic mice. However, whether interruption of CD40 signaling can retard the progression or even regress established lesions remains unknown. We report here that anti-CD40L antibody treatment of randomly assigned low-density lipoprotein receptor-deficient mice during the second half of a 26-week regimen of high-cholesterol diet did not regress, but did significantly reduce further evolution of established atherosclerotic lesions within the aortic arch and particularly the thoracic and abdominal aorta, as compared with control treatment (application of rat-IgG or saline; 13 weeks, continued high-cholesterol diet). In addition to limiting lesion progression, anti-CD40L treatment changed the composition of atheroma in manners thought to favor plaque stability, e.g., reduced relative content of macrophages and lipid, as well as increased relative content of smooth muscle cells and collagen. These data implicate CD40/CD40L as crucial mediators not only in the initial events of atherogenesis but also during the evolution of established atheroma. This study lends further support to the importance of this specific inflammatory signaling pathway in atherosclerosis and its complications.

Animals↗
PubMed2000

Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells.

Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear hormone receptor superfamily originally shown to play an important role in adipocyte differentiation and glucose homeostasis, is now known to regulate inflammatory responses. Given the importance of endothelial cell (EC)-derived chemokines in regulating leukocyte function and trafficking, we studied the effects of PPARgamma ligands on the expression of chemokines induced in ECs by the Th1 cytokine IFN-gamma. Treatment of ECs with PPARgamma activators significantly inhibited IFN-gamma-induced mRNA and protein expression of the CXC chemokines IFN-inducible protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC), whereas expression of the CC chemokine monocyte chemoattractant protein-1 was not altered. PPARgamma activators decreased IFN-inducible protein of 10 kDa promoter activity and inhibited protein binding to the two NF-kappaB sites but not to the IFN-stimulated response element ISRE site. Furthermore, PPARgamma ligands inhibited the release of chemotactic activity for CXC chemokine receptor 3 (CXCR3)-transfected lymphocytes from IFN-gamma-stimulated ECs. These data suggest that anti-diabetic PPARgamma activators might attenuate the recruitment of activated T cells at sites of Th1-mediated inflammation.

Chemokine CXCL10↗
PubMed2000

The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques.

Chemokines are chemotactic cytokines that activate and direct the migration of leukocytes. However, their role in modulating platelet function has not been shown. We studied the direct effect of chemokines on human platelets and found that of the 16 tested only stromal cell-derived factor (SDF)-1 induced platelet aggregation, accompanied by a rise in intracellular calcium. Platelets expressed the SDF-1 receptor, CXCR4, and an antibody to CXCR4 and pertussis toxin inhibited SDF-1-induced platelet aggregation, confirming that this effect is mediated through CXCR4, a Galphai-coupled receptor. SDF-1-induced platelet aggregation was also inhibited by wortmannin, LY294002, and genistein, suggesting that phosphatidylinositol 3-kinase and tyrosine kinase are likely involved in SDF-1-induced platelet aggregation. Because chemokines are produced from multiple vascular cells and atherosclerotic vessels are prone to develop platelet-rich thrombi, we examined the expression of SDF-1 in human atheroma. SDF-1 protein was highly expressed in smooth muscle cells, endothelial cells, and macrophages in human atherosclerotic plaques but not in normal vessels. Our studies demonstrate a direct effect of a chemokine in inducing platelet activation and suggest a role for SDF-1 in the pathogenesis of atherosclerosis and thrombo-occlusive diseases.

Antibodies, Monoclonal↗
PubMed2000

CD40 ligation induces tissue factor expression in human vascular smooth muscle cells.

Tissue factor (TF) instigates the extrinsic pathway of blood coagulation. Plaque disruption and exposure of circulating factor VII/VIIa to subendothelial procoagulants such as TF leads to intravascular thrombosis, a frequent cause of acute atherosclerotic events. Although the expression of TF in the intima of human atherosclerotic lesions is well established, little is known about the mechanisms of TF regulation in vascular smooth muscle cells (SMC). We demonstrate here that TF colocalizes with the receptor CD40 on lesional SMC within atherosclerotic lesions in situ. In cultured vascular SMC, ligation of CD40 with native CD40 ligand (CD40L) derived from activated T lymphocytes or recombinant human CD40L (rCD40L) induced the transient expression of TF on the cell surface (as determined by FACS analysis) in a concentration- and time-dependent manner and enhanced total cell-associated TF (as determined by ELISA). CD40L-induced TF on vascular SMC is functional and activates coagulation. In accordance with the increased TF activity, stimulation of vascular SMC with rCD40L did not affect either protein expression or activity of tissue factor pathway inhibitors. In summary, these findings demonstrate the potential of the CD40/CD40L signaling pathway to augment the procoagulant activity in human vascular SMC. Because TF and CD40 colocalize on lesional SMC in human atheroma, CD40/CD40L signaling may contribute to the TF expression and hence to increased thrombogenicity of plaques during the inflammatory responses of atherogenesis and arterial injury.

Arteriosclerosis↗