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Biomedical subjects

Patrick Rossignol

Publications and source records attributed to Patrick Rossignol.

At least 19 recordsLinked to original sources
PubMed2006

Low plasma levels of HSP70 in patients with carotid atherosclerosis are associated with increased levels of proteolytic markers of neutrophil activation.

BACKGROUND AND OBJECTIVE: Low levels of circulating HSP70 have been correlated with a high risk of coronary artery disease. We have measured HSP70 concentrations in carotid atherosclerotic patients and we have investigated the biological significance of the inverse relation between HSP70 levels and atherosclerosis. METHODS AND RESULTS: More HSP70 was released by healthy endarteries than by carotid atherosclerotic plaques, which was paralleled by a decrease in HSP70 plasma levels of patients with atherosclerosis relative to healthy subjects (ELISA). In contrast, elastase levels (ELISA) and activity (zymography) followed the opposite trend. HSP70 was proteolyzed when incubated with elastase in vitro or with atherosclerotic plaque samples, ex vivo, and this effect was prevented by elastase inhibitors (Western-blot). Finally, the levels of two markers of polymorphonuclear neutrophil activation (myeloperoxidase and matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin) followed a similar trend to that observed for elastase (ELISA), and a tight positive correlation existed between all three markers in conditioned media and in plasma. CONCLUSION: Low plasma levels of HSP70 are found in patients with atherosclerosis. Activated neutrophils could play a major role as a source of proteases able to degrade atheroprotective HSP70.

Aged↗
PubMed2006

Blunt renal trauma-induced hypertension: prevalence, presentation, and outcome.

BACKGROUND: Blunt renal trauma (RT) may cause hypertension. We assessed the frequency and mechanisms of RT, and blood pressure (BP) outcome after treatment. METHODS: We searched the records of all patients referred to our hypertension unit and included those of previously normotensive patients who developed hypertension within 6 months of RT. RESULTS: Ten of the 17,410 referred patients, with a median age of 26 years, developed hypertension 0 to 3 months after a well-documented RT. Median BP at referral was 170/107 mm Hg. Median glomerular filtration rate was 89 mL/min. Five patients had hematuria. Median kidney length was 107 mm on the damaged side and 114 mm on the opposite side. Renal artery lesions were present in six cases. A pattern of unilateral renin hypersecretion and contralateral suppression was present in five of eight cases with unilateral RT. Six patients underwent surgery. Seven months after referral, median BP was 128/79 mm Hg. The BP was <140/90 mm Hg without medication in one patient who did not undergo surgery and in three patients who did. CONCLUSIONS: Renal trauma is a rare cause of hypertension, mostly in young men. Hypertension is usually renin dependent and associated with parenchymal injury. The RT-induced hypertension may resolve spontaneously and is amenable to surgery.

Abdominal Injuries↗
PubMed2006

Blood pressure and renal outcomes in patients with kidney infarction and hypertension.

OBJECTIVE: To assess the causes and frequency of kidney infarction associated with hypertension, and the blood pressure and renal function outcomes. METHODS: We analyzed the records of patients with kidney infarction documented by angiography and referred to a hypertension unit. RESULTS: Spontaneous kidney infarction was documented in 55 of 18,287 patients and was associated with renal artery disease in 41 cases. Twenty-five patients had a longstanding history of hypertension at referral, and 30 patients presented with acute hypertension. Patients with acute hypertension were more likely to report a history of lumbar pain and to develop malignant hypertension than patients with longstanding hypertension; they also had higher plasma renin concentrations. Data for long-term follow-up after referral were available for 36 patients, including 15 patients who underwent surgery or renal artery angioplasty. From referral to most recent follow-up, the blood pressure decreased from 176/111 to 143/89 mmHg in patients with longstanding hypertension, and from 183/111 to 127/80 mmHg in those with acute hypertension (P = 0.007/0.041 for between-group differences). Three patients with acute hypertension had normal blood pressure without treatment at follow-up. Patients with long-term follow-up displayed no change in the glomerular filtration rate. CONCLUSION: Kidney infarction is a rare cause of hypertension, usually associated with renal artery lesions. In cases of kidney infarction with acute hypertension, the blood pressure outcome is favorable following intervention and/or medication, and hypertension may resolve spontaneously.

Acute Disease↗
PubMed2006

Plasminogen activator inhibitor-1 impairs plasminogen activation-mediated vascular smooth muscle cell apoptosis.

The role of plasminogen activator inhibitor-1 (PAI-1) in vascular smooth muscle cell (VSMC) apoptosis mediated by plasminogen activation was studied with the use of aorticVSMC derived from mice with deficiency of PAI-1 (PAI-1 (-/-) ), tissue-type (t-PA (-/-) ) or urokinase-type (u-PA (-/-) ) plasminogen activator or from wildtype (WT) mice with corresponding genetic background. Plasminogen incubated with confluent VSMC was activated in a concentration-dependent and saturable manner for all four cell types, with maximal activation rates that were comparable for WT, u-PA (-/-) and t-PA (-/-) cells, but about two-fold higher for PAI-1 (-/-) cells. Plasminogen activation was impaired by addition of the lysine analogue 6-aminohexanoic acid, and by addition of t-PA and u-PA neutralizing antibodies, suggesting that it depends on binding to cell surface COOH-terminal lysine residues, and on plasminogen activator activity. Morphological alterations consistent with apoptosis were observed much earlier in PAI-1 (-/-) than in WT VSMC. Without addition of plasminogen, the apoptotic index was similar for all four cell types, whereas after incubation with physiological plasminogen concentrations, it was greater in PAI-1 (-/-) VSMC, as compared to WT, t-PA (-/-) or u-PA (-/-) VSMC. Furthermore, the apoptotic rate paralleled the release of plasmin. Thus, plasmin-mediated apoptosis of VSMC occurs via plasminogen activation by either t-PA or u-PA and is impaired by PAI-1.

Animals↗
PubMed2006

Changes in urinary total metanephrine excretion in recurrent and malignant pheochromocytomas and secreting paragangliomas.

We quantified urinary excretion of total metanephrines (metanephrine plus normetanephrine) (UETM) in 261 patients with pheochromocytoma (PH) or secreting paraganglioma, before primary tumor resection. We then determined UETM 2 weeks after primary tumor resection and once per year thereafter. The tumor was considered benign in 242 patients and malignant in 19 patients. Patients with malignant tumors had higher UETM and tumor diameters, lower plasma epinephrine concentrations, and were more likely to have secreting paragangliomas than patients with benign tumors. In the 215 patients with a single-benign primary tumor, preoperative UETM and tumor diameter were significantly correlated. Thirty-six patients subsequently developed recurrences or new tumors, which were malignant in 18 cases. All recurrent or new tumors could be detected before the onset of symptoms, on the basis of an increase in metanephrine concentration. We followed one patient with von Hippel-Lindau disease and a new tumor for 50 months before reoperation and found that UETM and tumor diameter were significantly correlated. In patients with malignant tumors, the logarithm of UETM was significantly correlated with time, suggesting an exponential increase in tumor activity and, presumably, tumor burden. Urinary metanephrine excretion is a marker of tumor activity and a surrogate of tumor burden in patients with pheochromocytoma or secreting paraganglioma. UETM excretion could be used to assess treatment response in malignant cases.

Adrenal Gland Neoplasms↗
PubMed2006

Renewal of mural thrombus releases plasma markers and is involved in aortic abdominal aneurysm evolution.

Human abdominal aortic aneurysm (AAA) expansion has been linked to the presence of a mural thrombus. Here we explored the mechanism of the continual luminal renewal of this thrombus and its ability to release biological markers potentially detectable in plasma. We also explored the ability of platelet inhibition to pacify the thrombus and to limit aneurysm progression in an experimental model. Blood samples and mural thrombi were collected in 20 AAA patients. In parallel, segments of sodium dodecyl sulfate-decellularized guinea pig aorta were xenografted onto the abdominal aorta of 30 rats to induce aneurysms. Fifteen rats received abciximab treatment and fifteen received irrelevant immunoglobulins. Procoagulant activity and platelet activation markers (microparticles, sP-selectin, sGPV, sCD40L) were increased threefold to fivefold in eluates from the luminal thrombus layer compared to other layers. All these markers were increased twofold to fivefold in patients' plasma compared to matched controls (P < 0.005). In the rat model, abciximab reduced both thrombus area and aneurysmal enlargement (P < 0.05). Platelet aggregation is probably responsible for the renewal of the thrombus in AAA. The luminal thrombus released markers of platelet activation that could easily be detected in plasma. Platelet inhibition limited aortic aneurysm expansion in a rat model, providing new therapeutic perspectives in the prevention of AAA enlargement.

Abciximab↗
PubMed2006

Dual effect of apolipoprotein(a) on plasmin(ogen)-induced apoptosis through modulation of cell detachment of adherent cells.

Because of its structural homology with plasminogen, the apolipoprotein(a) [apo(a)] component of the athero-thrombogenic lipoprotein(a) [Lp(a)] particle inhibits plasminogen binding and activation onto fibrin as well as the subsequent fibrinolysis. In a similar manner, apo(a) may also interfere with plasmin(ogen)-induced cell detachment and apoptosis of adherent cells. To investigate this hypothesis, we studied the effect of a recombinant apo(a) [r-apo(a)] on plasminogen activation-induced apoptosis of vascular smooth muscle cells (VSMCs) and fibroblasts-like CHO-K1 cells. We demonstrate for the first time that apo(a) displays a concentration-dependent biphasic, enhancing/preventing effect on plasmin(ogen) induced cell detachment of VSMCs and CHO-K1 cells. Our results show that r-apo(a) binds to these cells with higher affinity than plasminogen [K(d) = 0.9 +/- 0.2 microM for plasminogen, K(d) = 1.77 +/- 0.34 nM for r-apo(a)] in a lysine-dependent manner. At high r-apo(a)/plasminogen ratios, their competitive interaction results in a partial inhibition of plasminogen activation by cell-bound t-PA. As a consequence, r-apo(a) prevents plasmin(ogen)-induced cell detachment and apoptosis. Surprisingly, at low r-apo(a)/plasminogen ratios, an enhancement in plasmin(ogen)-induced cell detachment and apoptosis was observed. This effect was shown to be "plasmin-selective" as r-apo(a) was unable to potentiate cell detachment induced by human neutrophil elastase and trypsin. Altogether these data are consistent with a new mechanism of apo(a)/plasmin(ogen) interactions that may contribute to the athero-thrombogenic potential of Lp(a).

Animals↗
PubMed2005

Reduced immunoregulatory CD31+ T cells in patients with atherosclerotic abdominal aortic aneurysm.

BACKGROUND: Cell-mediated immunity is considered to contribute to the pathogenesis of abdominal aortic aneurysms (AAA). In particular, infiltrating macrophages and CD8+ T lymphocytes participate in the destruction of the aortic wall extracellular matrix and smooth muscle cells. We surmise that these pathological events are controlled by circulating regulatory lymphocytes. METHODS AND RESULTS: Circulating CD4+/CD31+ cells were reduced in AAA patients (n=80, 8.9+/-0.6%) as compared with controls (n=69, 13.7+/-0.8%; P<0.001) and inversely proportional to AAA size. Exclusion of the aneurysm by an endoprothesis did not affect CD31+ T cell values. Reduction of blood CD4+/CD31+ cells was not attributable to their enrichment in AAA tissue. In contrast, CD8+/CD31+ cells were slightly reduced in the blood while increased in the aneurysmal tissue (29.2+/-0.5 versus 20.2+/-4.7% in blood, n=6; P<0.05). Remarkably, high percentages of CD4+/CD31+ cells were able to regulate proliferation and cytokine production of CD8+ lymphocytes, as well as CD8+ cell-mediated cytotoxicity of aortic smooth muscle cells (P<0.01). Finally, CD4+/CD31+ cells reduced the production and activity of metalloproteinase-9 by lipopolysaccharide-stimulated macrophages. CONCLUSIONS: Circulating CD4+/CD31+ T cells regulate macrophage and CD8+ T cell activation and effector function in the arterial wall. Their reduction might promote the development of AAA.

Aged↗
PubMed2005

Compliance of abdominal aortic aneurysms evaluated by tissue Doppler imaging: correlation with aneurysm size.

OBJECTIVES: Several studies have shown that an increase in abdominal aortic aneurysm (AAA) growth rate occurs when the diameter reaches 40 to 50 mm. AAA expansion is related to remodeling of the parietal extracellular matrix. The parietal mechanisms involved in this critical phase of sudden increase remain unexplained. Analysis of AAA wall movements and determination of AAA compliance may provide information about the constitution of the arterial wall. If a change in parietal wall motion somewhere between 40 and 50 mm could be shown, this would contribute to the understanding of the growth of AAA. Furthermore, it would provide a valuable additional parameter for AAA monitoring. This study had two aims: first, to evaluate the relationship between AAA compliance and maximum diameter using the tissue Doppler imaging system; and second, to test the hypothesis of a change in AAA behavior at around 45 mm in diameter. METHODS: Fifty-six patients with AAA (mean diameter, 39 mm) were prospectively investigated using the tissue Doppler imaging system, which provides information concerning arterial wall motion. Maximum mean segmental dilation (MMSD), segmental compliance, pressure strain elastic modulus (Ep), and stiffness were determined and related to the maximum diameter of AAA. Results After natural log transformation of all variables, there was a significant positive linear relationship between maximum diameter and both MMSD (P < .001) and segmental compliance (P < .001) but not with Ep or stiffness (P = .37 and .22, respectively). MMSD and segmental compliance were significantly higher in AAA > or = 45 mm than in AAA < 45 mm (P < .0002 and <. 004, respectively). Ep and stiffness tended to decrease in larger AAAs, but this was not statistically significant (P < .43 and .24, respectively). Dispersion of Ep and stiffness values seemed to be wider among AAA < 45 mm compared with those > or = 45 mm. CONCLUSION: Compliance parameters can easily be measured during routine AAA ultrasound monitoring using the tissue Doppler imaging system. The study showed an increase in MMSD and segmental compliance as well as a nonsignificant trend toward increased distensibility (decreased Ep and stiffness) with increased AAA diameter. A change in dispersion of AAA distensibility may appear around 45 mm in diameter, but a larger study will be needed to clarify this.

Abdominal Wall↗
PubMed2004

A paradoxical pro-apoptotic effect of thrombin on smooth muscle cells.

Whereas thrombin (below 10 nM) is a potent mitogen, recent studies report that exposure to higher doses of thrombin could lead to apoptosis of neurons and tumor cells. Our results show that prolonged exposure (> or = 24 h) to thrombin (50-100 nM) exerts a pro-apoptotic effect on cultured vascular smooth muscle cells (VSMCs). This phenomenon depends on thrombin serine-protease activity but is independent of PAR-1 and -4 activation and subsequent signaling. The parallel occurrence of cell retraction and cleavage of fibronectin suggests that thrombin-induced apoptosis is consecutive to pericellular proteolysis. These data point to a new potential action of thrombin in the cardiovascular system.

Animals↗
PubMed2004

[Influence of recent trials on essential arterial hypertension management].

Following recent trials, U.S (JNC7), European (ESH/ESC) and world (WHO) guidelines concerning the management of arterial essential hypertension have recently been updated. They indicate that hypertension treatment may succeed in preventing complications such as stroke or myocardial infarction. The therapeutic target is less than 140/90 mmHg (130/80 mmHg for diabetics). To reach this objective, a combination using a diuretic is required in almost all cases. Trials comparing the efficiency of "old drugs" such as diuretics or beta-blockers with "new drugs" such as ACEI or ARAII, or CCB observed minor differences in terms of cardiovascular outcomes. However, ACEI and ARAII appeared to be of particular efficiency in preventing heart and kidney failures.

Antihypertensive Agents↗
PubMed2004

Optimization of in vitro vascular cell transfection with non-viral vectors for in vivo applications.

BACKGROUND: Syngeneic vascular cells are interesting tools for indirect gene therapy in the cardiovascular system. This study aims to optimize transfection conditions of primary cultures of vascular smooth muscle cells (VSMCs) using different non-viral vectors and zinc as an adjuvant and to implant these transfected cells in vivo. METHODS: Non-liposomal cationic vectors (FuGene 6), polyethylenimines (ExGen 500), and histidylated polylysine (HPL) were used as non-viral vectors in vitro with secreted alkaline phosphatase (SEAP) as reporter gene. Transfection efficiency was compared in cultured rat, rabbit and human VSMCs and fibroblasts. Zinc chloride (ZnCl2) was added to optimize transfection of rat VSMCs in vitro which were then seeded in vivo. RESULTS: Much higher SEAP levels were obtained in rabbit cells with FuGene 6 (p <0.0001) at day 2 than in equivalent rat and human cells. Rat VSMCs transfected in vitro with FuGene 6 and ExGen 500 expressed higher SEAP levels than with HPL. In rat VSMCs, SEAP secretion was more than doubled by addition of 250 microM ZnCl2 (p <0.0001) for all vectors. Seeding of syngeneic VSMCs transfected under optimized conditions (FuGene 6/pcDNA3-SEAP +250 microM ZnCl2) into healthy Lewis rats using various routes or into post-infarct myocardial scar resulted in a peak of SEAP expression at day 2 and detectable activity in the plasma for at least 8 days. CONCLUSIONS: FuGene 6 is an efficient non-viral transfection reagent for gene transfer in somatic smooth muscle cells in vitro and ZnCl2 enhances its efficiency. This increased expression of the transgene product is maintained after seeding in vivo.

Alkaline Phosphatase↗
PubMed2004

Compliance of abdominal aortic aneurysms: evaluation of tissue Doppler imaging.

Expansion of abdominal aortic aneurysms (AAA) is due to remodeling of the parietal extra-cellular matrix and may lead to rupture. This remodeling is reflected by compliance which may be an indicator of AAA behavior and thus useful for clinicians. Tissue Doppler Imaging (TDI) is an ultrasonographic modality which allows wall motion measurements along an arterial segment. It has previously been evaluated in normal aortas and was then evaluated in thirty-five patients with AAA. Mean values (+/-standard deviation) characterizing maximum diameter AAA compliance were dilation 809 mum (+/-465), strain 2.2% (+/-1), pressure strain elastic modulus 3.94 10(5) Pa [3.25; 4.8] and stiffness 28.8 [24; 34.5], last values being expressed as geometric mean [interquartile range]. They were in accordance with those previously obtained with other systems. Segmental parameter values were maximum mean segmental dilation 534 mum (+/-305) and segmental compliance 14.6 (+/-8.3) 10(-2) mum/Pa. Reproducibility was appropriate for clinical studies. The TDI system is simple and reliable for measurement of AAA compliance, and compliance can easily be recorded during routine ultrasound control.

Abdominal Wall↗
PubMed2003

Protease nexin-1 inhibits plasminogen activation-induced apoptosis of adherent cells.

Degradation of adhesive glycoproteins by plasmin is implicated in cell migration. In this study, we further explored the role of plasminogen activation in cell adhesion and survival and show that uncontrolled plasminogen activation at the cell surface may induce cell detachment and apoptosis. We hypothesized that this process could be prevented in adherent cells by expression of protease nexin-1, a potent serpin able to inhibit thrombin, plasmin, and plasminogen activators. Using two- and three-dimensional culture systems, we demonstrate that Chinese hamster ovary fibroblasts constitutively express tissue-type plasminogen activator and efficiently activate exogenously added plasminogen in a specific and saturable manner (K(m) = 46 nm). The formation of plasmin results in proteolysis of fibronectin and laminin, which is followed by cell detachment and apoptosis. Protease nexin-1 expressed by transfected cells significantly inhibited the activity of plasmin and tissue-type plasminogen activator via the formation of inhibitory complexes and prevented cell detachment and apoptosis. In conclusion, protease nexin-1 may be an important anti-apoptotic factor for adherent cells. This cell model could be a useful tool to evaluate therapeutic agents such as serpins in vascular pathologies involving pericellular protease-protease inhibitor imbalance.

Amyloid beta-Protein Precursor↗
PubMed2003

Differentiated thick ascending limb (TAL) cultured cells derived from SV40 transgenic mice express functional apical NHE2 isoform: effect of nitric oxide.

Studying the apical Na/H exchanger NHE2 is difficult in the intact thick ascending limb (TAL) because of its weak expression and transport activity compared with the co-expressed NHE3. From a mouse transgenic for a recombinant plasmid adeno-SV(40) (PK4), we developed an immortalized TAL cell line, referred to as MKTAL, which selectively expresses NHE2 protein and activity. The immortalized cells retain the main properties of TAL cells. They have a stable homogeneous epithelial-like phenotype, express SV(40) T antigen and exhibit polarity with an apical domain bearing few microvilli and separated from lateral domains by typical epithelial-type junctional complexes expressing ZO1 protein. Tamm-Horsfall protein is present on the apical membrane. MKTAL cells express NHE2 and NHE1 proteins but not NHE3 and NHE4, whereby NHE2 protein is expressed selectively in the apical domain of the plasma membrane. NHE2 contributed about half of the total Na/H exchange activity. mRNAs for the Na-K-2Cl cotransporter-2 (NKCC2) and the anion exchangers AE2 and AE3 were also present. While acute exposure to NO donors did not alter NHE2 activity, chronic exposure inhibited NHE2 activity selectively and down-regulated NHE2 mRNA abundance. In conclusion, MKTAL cells retain structural and functional properties of their in vivo TAL counterparts and express functional NHE2 protein in the apical membrane, which may be inhibited by NO. Thus, MKTAL cells may be an appropriate model for studying the cellular mechanisms of NHE2 regulation.

Animals↗
PubMed2003

The serpin protease-nexin 1 is present in rat aortic smooth muscle cells and is upregulated in L-NAME hypertensive rats.

OBJECTIVE: Protease-nexin 1 (PN-1) belongs to the serpin superfamily and behaves as a specific thrombin inhibitor in the pericellular environment. Little is known about PN-1 expression and its regulation in the vascular system. In this study, we examined the expression of functionally active PN-1 in vitro in rat aortic smooth muscle cells and in vivo in rat arterial media and its regulation in hypertensive rats. METHODS AND RESULTS: The vascular PN-1 formed specific covalent complexes with thrombin involving the catalytic site of the protease, and heparin increased the formation of these complexes. We also demonstrated PN-1 in rat arterial media by immunohistochemical staining. Moreover, we examined in vivo vascular expression of PN-1 in a model of chronic hypertension induced by long-term administration of N(G)-nitro-L-arginine methyl ester (L-NAME). Marked increases in PN-1 mRNA (3-fold) and protein (2-fold) were observed after 2 months of hypertension. Increased expression of PN-1 in the vascular wall was associated with an increase in the formation of complexes between radiolabeled-thrombin and PN-1, indicating that PN-1 was functional. CONCLUSIONS: PN-1 may thus participate in the mechanisms that regulate thrombin activity in the vessel wall.

Administration, Oral↗