title: Cathepsin cleavage of sirtuin 1 in endothelial progenitor cells mediates stress-induced premature senescence.
abstract: Stress-induced premature senescence (SIPS) of endothelial cells (ECs) has emerged as a contributor to global EC dysfunction. One of the cellular abnormalities mechanistically linked to SIPS is lysosomal dysfunction. In this study, we examined the impact of a range of cardiovascular risk factors on the expression of sirtuin 1 (SIRT1), SIPS, and apoptosis, and we documented the role of SIRT1 in reduced EC and endothelial progenitor cell (EPC) viability. These findings were confirmed in mice with selective endothelial SIRT1 knockout. The effects of stressors could be partially mimicked by inducing lysosomal membrane permeabilization or inhibiting autophagy, and were reversed by a cathepsin inhibitor. We provide evidence that SIRT1 is an important substrate of cysteine cathepsins B, S, and L. An antioxidant/peroxynitrite scavenger, ebselen, prevented stress-induced SIRT1 depletion and subversion of autophagy by mitigating lysosomal dysfunction. In conclusion, our data advance the concept of "stem cell aging" by establishing the critical role of lysosomal dysfunction in the development of SIPS through the cathepsin-induced proteolytic cleavage of SIRT1, a mechanism linking cell stress to apoptosis and SIPS. Ebselen potently protects lysosomal membrane integrity, preventing cathepsin-induced cleavage of SIRT 1 in EPCs and blunting SIPS and apoptotic cell death induced by relevant cardiovascular stressors. The proposed mechanism of SIRT1 depletion in stress has all of the attributes of being a paradigm of SIPS of EPCs.
authors.affiliation: Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Xavier
authors.affiliation: Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Eliza
authors.initials: E
authors.lastname: Moskowitz-Kassai
authors.affiliation: Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Robert
authors.initials: R
authors.lastname: Chen
authors.affiliation: Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Connie Y
authors.initials: CY
authors.lastname: Lu
authors.affiliation: Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Kyle
authors.initials: K
authors.lastname: Sanduski
authors.affiliation: Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York.
authors.forename: Aleš
authors.initials: A
authors.lastname: Špes
authors.affiliation: Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, Ljubljana, Slovenia; Center of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Turk
authors.affiliation: Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York. Electronic address: Michael_goligorsky@nymc.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D001393:Azoles / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000209:etiology*; D002403:Cathepsins / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D024042:Collagen Type I / Q000494:pharmacology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular; D006861:Hydrogen Peroxide / Q000494:pharmacology; D054833:Isoindoles; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016566:Organoselenium Compounds / Q000494:pharmacology; D011994:Recombinant Proteins; D012307:Risk Factors; D056564:Sirtuin 1 / Q000172:deficiency / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects*; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D001393:Azoles; D024042:Collagen Type I; D054833:Isoindoles; D016566:Organoselenium Compounds; D011994:Recombinant Proteins; C042986:ebselen; C018524:N,N-dimethylarginine; D001120:Arginine; D006861:Hydrogen Peroxide; D002403:Cathepsins; D056564:Sirtuin 1