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HDL antielastase activity prevents smooth muscle cell anoikis, a potential new antiatherogenic property

Guadalupe Ortiz-Muñoz^*,,, Xavier Houard^*,,, Jose-Luis Martín-Ventura^*,,, Brian Y. Ishida, Stéphane Loyau^*,,, Patrick Rossignol^¶,||,#,**,,, Juan-Antonio Moreno^*,,, John P. Kane, Robert J. Chalkley, Alma L. Burlingame, Jean-Baptiste Michel^*,, and Olivier Meilhac^*,,

^* INSERM, U698, Paris, France;

University of Paris 7, Paris, France;

Centre Hospitalier Universitaire X. Bichat, Paris, France;

University of California, San Francisco, San Francisco, California, USA;

^¶ Centre Hospitalier Universitaire de Nancy, Hôpital Jeanne d’Arc, Dommartin-lès-Toul, France;

^|| INSERM, Centre d’Investigation Clinique de Nancy CIC-P 9501, Dommartin-lès-Toul, France;

^# Faculté de Médecine, Nancy-Université, Vandoeuvre-les-Nancy, France;

^** INSERM, U961, Vandoeuvre-les-Nancy, France;

Service de Médecine Vasculaire et Hypertension artérielle and Centre d’Investigation Clinique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; and

Faculté de Médecine René Descartes Paris 5, Paris, France

¹ Correspondence: INSERM U698, Hôpital X. Bichat, 46, rue Henri Huchard, 75877 Paris cedex 18, France. E-mail: olivier.meilhac{at}inserm.fr

Various studies using proteomic approaches have shown that HDL can carry many proteins other than its constitutive apolipoprotein A-I (apoA-I). Using mass spectrometry and Western blotting, we showed the presence of ₁-antitrypsin (AAT) (SERPINA1, serpin peptidase inhibitor, clade A, an elastase inhibitor) in HDL, isolated either by ultracentrifugation or by selected-affinity immunosorption using an anti-apoA-I column. Furthermore, we report that HDL possesses potent antielastase activity. We further showed that only HDL but not LDL is able to bind AAT. HDL-associated AAT was able to inhibit extracellular matrix degradation, cell detachment, and apoptosis induced by elastase in human vascular smooth muscle cells (VSMCs) and in mammary artery cultured ex vivo. Degradation of fibronectin by elastase used as a marker of pericellular proteolysis was prevented by addition of HDL. Elastase present in aortic abdominal aneurysm (AAA) thrombus samples was also able to induce apoptosis of VSMCs in culture. This phenomenon was prevented by addition of HDL but not of LDL. Finally, we report that the proportion of AAT in HDL isolated from patients with an AAA is decreased relative to that from matched control subjects, suggesting a reduced capacity of HDL to inhibit elastase in these patients. In conclusion, our data provide evidence of a new potential antiatherogenic property of HDL attributable to AAT and its antielastase activity.—Ortiz-Muñoz, G., Houard, X., Martín-Ventura, J.-L., Ishida, B. Y., Loyau, S., Rossignol, P., Moreno, J.-A., Kane, J. P., Chalkley, R. J., Burlingame, A. L., Michel, J.-B., Meilhac, O. High-density lipoprotein antielastase activity prevents smooth muscle cell anoikis, a potential new antiatherogenic property.