Long Term Stabilization of Expanding Aortic Aneurysms by a Short Course of Cyclosporine A through Transforming Growth Factor-Beta Induction

Abdominal aortic aneurysms (AAAs) expand as a consequence of extracellular matrix destruction, and vascular smooth muscle cell (VSMC) depletion. Transforming growth factor (TGF)-beta 1 overexpression stabilizes expanding AAAs in rat. Cyclosporine A (CsA) promotes tissue accumulation and induces TGF -beta1 and, could thereby exert beneficial effects on AAA remodelling and expansion. In this study, we assessed whether a short administration of CsA could durably stabilize AAAs through TGF-beta induction. We showed that CsA induced TGF-beta1 and decreased MMP-9 expression dose-dependently in fragments of human AAAs in vitro, and in animal models of AAA in vivo. CsA prevented AAA formation at 14 days in the rat elastase (diameter increase: CsA: 131.9±44.2%; vehicle: 225.9±57.0%, P = 0.003) and calcium chloride mouse models (diameters: CsA: 0.72±0.14 mm; vehicle: 1.10±0.11 mm, P = .008), preserved elastic fiber network and VSMC content, and decreased inflammation. A seven day administration of CsA stabilized formed AAAs in rats seven weeks after drug withdrawal (diameter increase: CsA: 14.2±15.1%; vehicle: 45.2±13.7%, P = .017), down-regulated wall inflammation, and increased αSMA-positive cell content. Co-administration of a blocking anti-TGF-beta antibody abrogated CsA impact on inflammation, αSMA-positive cell accumulation and diameter control in expanding AAAs. Our study demonstrates that pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the degradation/repair balance towards healing

L' autofiction dans l'oeuvre de Colette

Malgré le début d institutionnalisation dont bénéficie depuis 2003 l autofiction, son sens est encore à l heure actuelle sujet à polémique. Serge Doubrovsky qui est l inventeur de cette forme littéraire - qu en dernier ressort il appréhende comme une variante de l autobiographie - considère Colette comme une pionnière illustrant sa conception. Notre thèse s inscrit dans une telle perspective conceptuelle, chronologiquement paradoxale. En effet, l examen attentif de l œuvre de Colette nous conduit à l inscrire globalement dans un espace autofictionnel. Colette n a d ailleurs jamais souscrit de pacte autobiographique, et demeure dans ce domaine volontairement ambiguë. Néanmoins elle n est pas pour autant indifférente aux considérations théoriques d ordre autobiographique, et nous nous sommes fixé pour objectif d expliquer les motivations qui l ont poussée à privilégier l autofiction plutôt que l autobiographie canonique comme mode d expression de soi. Sans doute pouvons-nous penser que ce choix tient à l originalité de l autofiction qui se définit plus particulièrement comme une recherche de soi par l écrivain, recherche d un sujet insaisissable en son essence, ainsi que d un espace-temps oscillant entre rêve et réalité, projection plutôt que rétrospection.Although the genre autofiction has been accepted by the literary Establishment since 2003, its exact meaning is still open to controversy today. Serge Doubrovsky, who invented this particular form of literature, views it essentially as a variant of autobiography. He regards Colette as being the first writer to put his particular theory into practice. Our thesis employs the theoretical perspective of autofiction, with all the chronological paradox that the term implies. Indeed, a close examination of Colette s work prompts us to situate it globally in a autofictional sphere. Colette never actually subscribed to any autobiographical pact, maintaining a deliberate ambiguity in this regard, but nevertheless she cannot be accused of indifference to theoretical autobiographical considerations, and we have set out to explain the reasons why she favoured autofiction rather than straightforward autobiography as a means of self-expression in this study. One could no doubt put her choice down to the originality of autofiction, a genre that Colette more specifically defines as self-searching, the quest for an essentially elusive subject and a space-time oscillation between dream and reality which has more to do with projection than retrospection.LE MANS-BU Lettres (721812108) / SudocSudocFranceF

Apports a la connaissance du récepteur B2 humain de la bradykinine (influence des modifications post-traductionnelles et des partenaires moléculaires)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

A model of hypoxia-reoxygenation on isolated adult mouse cardiomyocytes: characterization, comparison with ischemia-reperfusion, and application to the cardioprotective effect of regular treadmill exercise.

International audienceThe use of in vitro experimental models of hypoxia-reoxygenation (H/R) that mimic in vivo ischemia-reperfusion represents a powerful tool to investigate cardioprotective strategies against myocardial infarction. Most in vitro studies are performed using neonatal cardiac cells or immortalized embryonic cardiac cell lines which may limit the extrapolation of the results. We developed an H/R model using adult cardiomyocytes freshly isolated from mice and compared its characteristics to the in vivo ischemia-reperfusion conditions. First, cell death was assessed at different values of pH medium during hypoxia (6.2 vs 7.4) to simulate extracellular pH during in vivo ischemia. Cardiomyocyte mortality was aggravated with hypoxia under acidic pH. We next evaluated the relationship between the duration of hypoxia and cell death. Hypoxia time-dependently reduced myocyte viability (-24%, -36%, -53%, and -74% with 1, 1.5, 2, and 3 hours of hypoxia followed by 17 hours of reoxygenation, respectively). We then focused on the duration of reoxygenation as cardioprotective strategies have been reported to have different effects with short and long durations of reperfusion. We observed that cardiomyocyte mortality was increased when the duration of reoxygenation was increased from 2 h to 17 hours. Finally, we used our characterized model to investigate the cardioprotective effect of regular treadmill exercise. Myocyte viability was significantly greater in exercised when compared to sedentary mice (44% and 26%, respectively). Similarly, mice submitted to in vivo ischemia-reperfusion elicited infarct sizes reaching 27%, 43%, and 55% with 20, 30, and 45 minutes of coronary artery occlusion. In addition, infarct size was significantly reduced by exercise. In conclusion, this H/R model of cardiomyocytes freshly isolated from adult mice shows similar characteristics to the in vivo ischemia-reperfusion conditions. The comparison of in vivo and in vitro settings represents a powerful approach to investigate cardioprotective strategies and to distinguish between direct and indirect cardiomyocyte-dependent mechanisms

CsA induction of AAA stabilization is mediated by TGF-beta.

<p>A. Effect of the administration of a blocking antibody against active TGF-beta on the stabilizing effect of CsA on aortic diameter of expanding AAAs in rats. B and C. Impact of anti-TGF-beta blocking antibody on αSMA-positive cell density (A) and monocyte/macrophage infiltration (C) in rat AAAs treated with CsA. Open circles represent individual values and closed circles represent means±SD. **P<.01 <i>vs</i> isotype antibody.</p

CsA preserves VSMC and elastin content and modulates TGF-beta1 and MMP-9 expression in mouse AAAs.

<p>A. Representative anti-αSMA immunostaining performed on AAA cross sections from vehicle- or CsA-treated rats, 14 days after elastase perfusion (red: αSMA staining; blue : nuclei). B, C. Representative anti-αSMA (B) or elastin fibers (C) staining (<i>right</i>) and computer-assisted quantification (<i>left</i>) performed on AAA cross sections from vehicle- or CsA-treated mice at 14 days. D. Representative anti-active TGF-beta1 staining <i>(right)</i> and computer-assisted quantification <i>(left)</i> performed on AAA cross sections from vehicle- and CsA-treated mice at 14 days. E. ELISA quantification of MMP-9 on AAA extracts from vehicle- and CsA-treated mice. Results are reported to the total protein level. Open circles represent individual values from vehicle- and CsA-treated mice and closed circles represent means±SD. *P<.05, **P<.01 <i>vs</i> vehicle. NI : neointima; ILT: intraluminal thrombus. Scale bars : 50 µm.</p