[Apoptosis in the cardiovascular system].
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Apoptosis↗
Biomedical subjects
A Tedgui
Publications and source records attributed to A Tedgui.
Severe atherosclerosis and hypoalphalipoproteinemia in the staggerer mouse, a mutant of the nuclear receptor RORalpha.
BACKGROUND: Hypoalphalipoproteinemia is the most common lipoprotein abnormality in patients with coronary artery disease, yet its causes are unknown. METHODS AND RESULTS: We show that the homozygous staggerer (sg/sg) mutant mouse, which carries a deletion within the nuclear receptor RORalpha gene, develops severe atherosclerosis when maintained on an atherogenic diet. In addition, sg/sg mice display a profound hypoalphalipoproteinemia, which is associated with decreased plasma levels of the major HDL proteins, apolipoprotein (apo) A-I and apoA-II. This decrease in HDL levels in sg/sg mice is due to lowered apoA-I gene expression in the intestine but not in the liver. ApoA-II gene expression is unaffected. CONCLUSIONS: These results suggest that the RORalpha gene contributes to the plasma HDL level and susceptibility to atherosclerosis.
Animals↗
Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators.
Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.
Acute-Phase Proteins↗
Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure.
BACKGROUND: It has been suggested that oxidant stress may play a role in the pathophysiology of heart failure. However, no definitive information is available because most previous approaches used to measure oxidant stress are nonspecific, inaccurate, and unreliable. METHODS AND RESULTS: To evaluate oxidant stress in the heart, we measured pericardial fluid levels of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a specific and quantitative marker of oxidant stress in vivo, in a series of 51 consecutive patients with ischemic and/or valvular heart disease referred for cardiac surgery. Pericardial levels of 8-iso-PGF2alpha were correlated with the functional severity of heart failure (NYHA classification) and with echocardiographic indices of ventricular dilatation measured by independent physicians. Pericardial levels of 8-iso-PGF2alpha were significantly increased in patients with symptomatic heart failure compared with asymptomatic patients and gradually increased with the functional severity of heart failure (P=.0003). In addition, pericardial levels of 8-iso-PGF2alpha were significantly correlated with left ventricular end-diastolic and end-systolic diameters (P=.008 and .026, respectively). CONCLUSIONS: Pericardial levels of 8-iso-PGF2alpha increase with the functional severity of heart failure and are associated with ventricular dilatation. These data suggest an important role for in vivo oxidant stress on ventricular remodeling and the progression to heart failure.
Adult↗
Aminoguanidine prevents age-related arterial stiffening and cardiac hypertrophy.
Aging is associated with cardiac hypertrophy and arterial stiffening possibly associated with accumulation of advanced glycation end products (AGEs). We evaluated the effect of aminoguanidine, an inhibitor of AGE production, on end-stage alterations of renal and cardiovascular systems. Normotensive WAG/Rij rats were treated from 24 to 30 mo with aminoguanidine and compared with a control group. Aminoguanidine did not modify body and kidney weights but prevented the age-related cardiac hypertrophy (heart weight: 1276 +/- 28 mg and 1896 +/- 87 mg in 24- and 30-mo-old control animals and 1267 +/- 60 mg in 30-mo-old treated rats, P < 0.01). The increase in mesangial surface in aging rats was reduced by 30% by aminoguanidine. Collagen content of the arterial wall increased between 24 and 30 mo whereas elastin content, media thickness, and smooth muscle cell number remained unchanged. Aminoguanidine did not affect these parameters; however, the age-related increase in aortic impedance (12.4 +/- 1.4 and 18.2 +/- 1.9 10(3).dyne.sec.cm-5 in control 24- and 30-mo-old rats, P < 0.01) and the decrease in carotid distensibility (0.79 +/- 0.11 and 0.34 +/- 0. 07 mm Hg-1 in control 24- and 30-mo-old rats, P < 0.01) were prevented by aminoguanidine. The prevention of arterial stiffening and cardiac hypertrophy in the absence of changes in collagen and elastin content suggests that the effect of aminoguanidine is related to a decrease in the AGE-induced cross-linking of the extracellular matrix.
Aging↗
Rate of apoptosis in human atherosclerosis.
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Apoptosis↗
Increased calcium 45 fluxes in histologically abnormal human ascending aorta.
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Adult↗
External stenting & atherosclerosis.
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Animals↗
Intraluminal pressure is essential for the maintenance of smooth muscle caldesmon and filamin content in aortic organ culture.
Different forms of mechanical stimulation are among the physiological factors constantly acting on the vessel wall. We previously demonstrated that subjecting vascular smooth muscle cells (VSMCs) in culture to cyclic stretch increased the expression of high-molecular-weight caldesmon, a marker protein of a differentiated, contractile, VSMC phenotype. In the present work the effects of mechanical factors, in the form of circumferential stress and shear stress, on the characteristics of SM contractile phenotype were studied in an organ culture of rabbit aorta. Application of an intralumininal pressure of 80 mm Hg to aortic segments cultured in Dulbecco's modified Eagle's medium containing 20% fetal calf serum for 3 days prevented the decrease in high-molecular-weight caldesmon content (70+/-4% of initial level in nonpressurized vessel, 116+/-17% at 80 mm Hg) and filamin content (80+/-5% in nonpressurized vessel, 100+/-2% at 80 mm Hg). SM myosin and low-molecular-weight caldesmon contents showed no dependence on vessel pressurization. Neither endothelial denudation nor alteration of intraluminal flow rates affected marker protein content in 3-day vessel culture, thus excluding the possibility of any shear or endothelial effects. Maintenance of high high-molecular-weight caldesmon and filamin levels in the organ cultures of pressurized and stretched vessels demonstrates the positive role of mechanical factors in the control of the VSMC differentiated phenotype.
Animals↗
Resistance to endotoxin shock in spontaneously hypertensive rats.
Septic shock involves systemic vasodilation mediated by proinflammatory cytokines. In essential hypertension, vascular and immune dysfunctions are closely associated. The response of hypertensive animals compared with normotensive controls to endotoxin (lipopolysaccharide; LPS) challenge is not known. Age-matched (12 weeks) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were exposed to intravenous injection of 10 mg/kg LPS. Survival rate at 24 hours was markedly higher in SHR than in WKY (12 of 15 and 3 of 15, respectively; P<0.01). Survival of LPS-injected SHR was not related to their hypertension because hydralazine-treated SHR with normalized pressure had similar survival rates, and WKY made hypertensive by clipping of one renal artery showed fatality similar to that of normotensive WKY. Continuous arterial pressure and sequential plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured in LPS-treated SHR and WKY. Both the duration of the delayed hypotensive phase and the systemic release of IL-6 were much lower in SHR than WKY, whereas both acute hypotension and plasma TNF peak were equivalent. We further explored in vitro the inflammatory response and showed that LPS-activated whole blood from SHR produced less TNF and IL-6 than WKY LPS-activated whole blood. Our results indicate that SHR have a greater ability to resist endotoxic shock than WKY. This is not related to their hypertension but is associated with an attenuated inflammatory response to LPS.
Animals↗
Signal transduction of mechanical stresses in the vascular wall.
The vascular wall is constantly subjected to a variety of mechanical forces in the form of stretch (tensile stress), due to blood pressure, and shear stress, due to blood flow. Alterations in either of these stresses are known to result in vascular remodeling, an adaptation characterized by modified morphology and function of the blood vessels, allowing the vessels to cope with physiological or pathological conditions. The processes involved in vascular remodeling include cellular hypertrophy and hyperplasia, as well as enhanced protein synthesis or extracellular matrix protein reorganization. In vitro studies using vascular cells have attempted to identify the mechanisms behind structural alterations. Possible pathways include ion channels, integrin interaction between cells and the extracellular matrix, activation of various tyrosine kinases (such as c-Src, focal adhesion kinase, and mitogen-activated protein kinases), and autocrine production and release of growth factors. These pathways lie upstream of de novo synthesis of immediate response genes and total protein synthesis, both of which are likely to be involved in the process of vascular remodeling.
Animals↗
[Role of the endothelium in atherosclerosis].
Endothelial injury has long been considered as a prerequisite for atherosclerotic plaque formation. Experimental and clinical studies have proven that during lesion development the endothelium is morphologically intact, but its phenotype is changed to an activated state, which favours the chronic inflammatory process leading to atherosclerotic disease. Endothelium is involved in atherosclerosis in several manners including: 1. subendothelial accumulation of atherogenic lipoproteins, through the barrier properties of the endothelium; 2. intimal accumulation of macrophages, through recruitment and adhesion of monocytes, when endothelial cells are activated; 3, vasospasm, when its vasodilatory properties are altered; 4, thrombus formation, when the endothelium is eroded.
Arteriosclerosis↗
Transcriptional regulation of apolipoprotein A-I gene expression by the nuclear receptor RORalpha.
Since elevated concentrations of plasma high density lipoprotein (HDL) and its major apolipoprotein (apo), apoA-I, confer protection against atherosclerosis, considerable research efforts have focussed on the identification of factors regulating apoA-I gene expression in an attempt to increase its production. Nuclear receptors are interesting candidates because they are transcription factors whose activity is ligand-dependent. In the present study we identified the orphan receptor RORalpha1 as an activator of apoA-I gene transcription. In apoA-I-expressing intestinal Caco-2 cells, overexpression of the RORalpha1, but not the RORalpha2 or RORalpha3 isoforms, increased rat apoA-I gene transcription. Deletion and site-directed mutagenesis experiments identified a functional ROR-responsive element (RORE) in the rat and mouse apoA-I gene promoters, which overlaps with the TATA box. Gel shift experiments indicated that this RORE binds the RORalpha1 isoform, but not the RORalpha2 or RORalpha3 isoforms. Furthermore, compared with wild type mice, apoA-I mRNA levels were significantly lower in small intestines of staggerer mice homozygous for a deletion in the RORalpha gene. In addition, reverse transcriptase-polymerase chain reaction analysis revealed the expression of RORalpha in small intestinal epithelium and in Caco-2 cells. These data indicate a novel, physiological role for RORalpha1 in the regulation of genes involved in lipid and lipoprotein metabolism and possibly in the development of metabolic diseases, such as atherosclerosis.
Animals↗
Colocalization of CPP-32 with apoptotic cells in human atherosclerotic plaques.
BACKGROUND: Apoptosis that has been reported in human atherosclerosis may contribute to the remodeling of atherosclerotic plaques. The identification of specific markers for apoptosis in these plaques would permit the development of specific therapeutic strategies to limit their progression. Cysteine protease CPP-32 is essential for apoptotic death in mammalian cells and appears to be an attractive candidate. METHODS AND RESULTS: We studied 12 atherosclerotic plaques from 12 patients who underwent carotid endarterectomy. Apoptosis was analyzed by in situ end labeling of fragmented DNA (TUNEL method) and corroborated by the presence of DNA fragmentation in agarose gel electrophoresis. CPP-32 was detected with the use of a specific monoclonal antibody, and its expression was compared with that of interleukin-1beta-converting enzyme (ICE). We showed that CPP-32 was highly expressed in 10 of 12 atherosclerotic plaques and that it colocalized with apoptotic cells. Expression of ICE generally paralleled that of CPP-32, but ICE was also detected in plaques negative for CPP-32 and showing no apoptosis. CONCLUSIONS: CPP-32 is highly expressed within human atherosclerotic plaques and is closely related to apoptosis. This finding suggests that CPP-32 may be the ICE-like enzyme responsible for apoptosis in human atherosclerosis and opens new perspectives for the development of therapeutic strategies to alter the progression of this disease.
Apoptosis↗
Native and gamma radiolysis-oxidized lipoprotein(a) increase the adhesiveness of rabbit aortic endothelium.
Accumulation of monocyte-derived foam cells in the arterial intima is a major event in the development of atherogenesis. We have examined whether native and oxidized lipoprotein(a) (Lp(a)) can induce adhesion of monocytic cells to aortic endothelium. The extensive oxidation of paired samples of Lp(a) and low-density lipoprotein (LDL) was achieved by O2.-/OH. free radicals produced by gamma radiolysis of water, leading to similar values for the formation of peroxidation markers (conjugated dienes, TBARS, 8-epi-PGF2alpha) for both Lp(a) and LDL. Rabbit aortic segments were incubated for 5 h in the presence of equimolar concentrations of native and oxidized preparations of Lp(a) and LDL (125 micromol cholesterol/l, corresponding to 40 and 30 mg protein/l for Lp(a) and LDL, respectively). The aortic segments were incubated with rhodamin-isothiocyanate labeled U937 monocytic cells for 30 min and cell adhesion was quantified by fluorescent microscopy. Native Lp(a), and to a larger extent oxidized Lp(a), significantly increased U937 cell adhesion by 2.3 and 2.7 fold compared to controls (P < 0.005 and P < 0.001, respectively). Monocytic cell adhesion was also increased by native LDL (1.6 fold, P < 0.005), and to a greater extent by oxidized LDL (2.3 fold, P < 0.001). Thus native Lp(a) enhances the adhesive properties of the arterial endothelium which may account for its proatherogenic action. Furthermore, our results show that oxidized Lp(a), as well as oxidized LDL, are potent stimuli of monocyte adhesion to endothelial cells.
Animals↗
Regulation of the expression of cyclooxygenase-2 by nitric oxide in rat peritoneal macrophages.
Activation of rat peritoneal macrophages by LPS resulted in time-dependent production of nitric oxide and enhancement of cyclooxygenase (Cox) activity. This stimulation was accompanied by increased expression of inducible enzymes, NO synthase, and Cox-2, contrasting with no variation in constitutive Cox-1. Inhibition of NO production in LPS-treated macrophages by either the L-arginine analogue N(G)-monomethyl-L-arginine (L-NMMA) or aminoguanidine was accompanied by an additional enhancement of Cox activity parallel to the expression of Cox-2 protein analyzed by Western blot. Addition of NO donors (3-morpholinosydnonimine (Sin-1), sodium nitroprusside, or S-nitrosoglutathione) reversed the effects of L-NMMA, confirming the role of NO on Cox-2 expression. Specific immunoprecipitation of Cox-2 showed a pattern of protein expression similar to that observed in intact cells. Enzyme activity tested on the immunoprecipitates was correlated with the enzyme mass. In contrast, there was no variation in immunoprecipitated Cox-1 protein or in activity. Levels of mRNA for Cox-2 were increased in macrophages stimulated by LPS in the presence of L-NMMA compared with LPS alone. Metabolic labeling using [35S]methionine showed that inhibition of NO formation resulted in enhanced de novo synthesis of the 35S-labeled Cox-2. The amount of Cox-2 protein induced in the presence or absence of L-NMMA did not change for at least 6 h, suggesting that NO does not modify the t1/2 of the enzyme. These results provide evidence that NO participates in PG production by negative regulation of Cox-2 expression.
Animals↗
Increased pressure induces sustained protein kinase C-independent herbimycin A-sensitive activation of extracellular signal-related kinase 1/2 in the rabbit aorta in organ culture.
The 42- and 44-kD mitogen-activated protein kinases, also referred to as extracellular signal-related kinase (ERK) 2 and 1, respectively, may be transiently activated by stretching vascular smooth muscle cells (VSMCs). Using an organ culture model of rabbit aorta, we studied short- and long-term ERK1/2 activation by intraluminal pressure (150 mm Hg). Activation of ERK1/2 was biphasic: it reached a maximum (217.5 +/- 8.4% of control) 5 minutes after pressurizing and decreased to 120.7 +/- 5.1% of control after 2 hours. Furthermore, after 24 hours of pressurizing, ERK1/2 activity was as high (241.8 +/- 14.7% of control) as in the acute phase. Long-term pressure-induced ERK1/2 activation correlated with stimulation of tyrosine phosphorylation of proteins in the 125- to 140-kD range. Neither protein kinase C inhibitors (1 mumol/L staurosporine or 50 mumol/L bisindolylmaleimide-I) nor tyrosine kinase inhibitors (50 mumol/L tyrphostin A48 or 50 mumol/L genistein) affected pressure-induced ERK1/2 activation. However, the Src-family tyrosine kinase inhibitor herbimycin A (500 nmol/L) did reduce both 5-minute (by 92 +/- 8%) and 24-hour (by 63 +/- 7%) pressure-induced ERK1/2 activation. Thus, our results demonstrate a sustained activation of ERK1/2 and tyrosine kinases by intraluminal pressure in the arterial wall. Pressure-induced ERK1/2 activation is PKC independent and Src-family tyrosine kinase dependent and possibly includes activation of extracellular matrix-associated tyrosine kinases.
Animals↗
Evidence of apoptosis in arrhythmogenic right ventricular dysplasia.
BACKGROUND: Arrhythmogenic right ventricular dysplasia, a disorder that may lead to severe ventricular arrhythmias and sudden death, is characterized by the progressive replacement of myocardial cells by fat and fibrous tissue. We examined whether the loss of myocardial cells in this disease could result from cell death by apoptosis (programmed cell death). METHODS: Specimens obtained at autopsy from the right ventricular myocardium of eight patients with arrhythmogenic right ventricular dysplasia and four age-matched normal subjects were analyzed. To identify individual cells undergoing apoptosis, we performed in situ end-labeling of fragmented DNA on paraffin sections using biotinylated deoxyuridine triphosphate and the enzyme terminal deoxynucleotidyl transferase. We also examined the level of expression of CPP-32, a cysteine protease required for apoptotic cell death in mammalian cells, using immunohistochemical techniques. RESULTS: Apoptosis was detected in the right ventricular myocardium of six of the eight patients with arrhythmogenic right ventricular dysplasia and was absent in the controls. High levels of expression of CPP-32 were associated with positive in situ end-labeling of fragmented DNA. CONCLUSIONS: These results indicate that apoptotic myocardial cell death occurs in arrhythmogenic right ventricular dysplasia and may contribute to the loss of myocardial cells in this disorder.
Adult↗