title: Peroxisome proliferator-activated receptor gamma induces apoptosis and inhibits autophagy of human monocyte-derived macrophages via induction of cathepsin L: potential role in atherosclerosis.
abstract: Macrophages play a pivotal role in the pathophysiology of atherosclerosis. These cells express cathepsin L (CatL), a cysteine protease that has been implicated in atherogenesis and the associated arterial remodeling. In addition, macrophages highly express peroxisome proliferator-activated receptor (PPAR) γ, a transcription factor that regulates numerous genes important for lipid and lipoprotein metabolism, for glucose homeostasis, and inflammation. Hence, PPARγ might affect macrophage function in the context of chronic inflammation such as atherogenesis. In the present study, we examined the effect of PPARγ activation on the expression of CatL in human monocyte-derived macrophages (HMDM). Activation of PPARγ by the specific agonist GW929 concentration-dependently increased the levels of CatL mRNA and protein in HMDM. By promoter analysis, we identified a functional PPAR response element-like sequence that positively regulates CatL expression. In addition, we found that PPARγ-induced CatL promotes the degradation of Bcl2 without affecting Bax protein levels. Consistently, degradation of Bcl2 could be prevented by a specific CatL inhibitor, confirming the causative role of CatL. PPARγ-induced CatL was found to decrease autophagy through reduction of beclin 1 and LC3 protein levels. The reduction of these proteins involved in autophagic cell death was antagonized either by the CatL inhibitor or by CatL knockdown. In conclusion, our data show that PPARγ can specifically induce CatL, a proatherogenic protease, in HMDM. In turn, CatL inhibits autophagy and induces apoptosis. Thus, the proatherogenic effect of CatL could be neutralized by apoptosis, a beneficial phenomenon, at least in the early stages of atherosclerosis.
authors.affiliation: Unité de Recherche, Vieillissement, Stress et Inflammation, Université Pierre et Marie Curie, 75252 Paris, Cedex 5, France.
authors.forename: Dler Faieeq Darweesh
authors.initials: DFD
authors.lastname: Mahmood
authors.affiliation: Unité de Recherche, Vieillissement, Stress et Inflammation, Université Pierre et Marie Curie, 75252 Paris, Cedex 5, France.
authors.forename: Imene
authors.initials: I
authors.lastname: Jguirim-Souissi
authors.affiliation: Unité de Recherche, Vieillissement, Stress et Inflammation, Université Pierre et Marie Curie, 75252 Paris, Cedex 5, France.
authors.forename: El-Hadri
authors.initials: EH
authors.lastname: Khadija
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097, CNRS/Université de Nice Sophia Antipolis, 06560 Valbonne, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blondeau
authors.affiliation: Unité de Recherche, Vieillissement, Stress et Inflammation, Université Pierre et Marie Curie, 75252 Paris, Cedex 5, France.
authors.forename: Vimala
authors.initials: V
authors.lastname: Diderot
authors.affiliation: Laboratoire de Biochimie, Faculté des Sciences de Oujda, 60000 Oujda, Morocco.
authors.forename: Souliman
authors.initials: S
authors.lastname: Amrani
authors.affiliation: Laboratoire de Biochimie, Faculté de Médecine de Monastir, 5000 Monastir, Tunisia, and.
authors.forename: Mohamed-Naceur
authors.initials: MN
authors.lastname: Slimane
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Syrovets
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
authors.affiliation: Unité de Recherche, Vieillissement, Stress et Inflammation, Université Pierre et Marie Curie, 75252 Paris, Cedex 5, France,. Electronic address: mustapha.rouis@snv.jussieu.fr.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Rouis
mesh_terms: D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001343:Autophagy; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C534281:CTSL protein, human; D056668:Cathepsin L