title: Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening.
abstract: Arterial stiffening is a hallmark of aging and risk factor for cardiovascular disease, yet its regulation is poorly understood. Here we use mouse modeling to show that matrix metalloproteinase-12 (MMP12), a potent elastase, is essential for acute and chronic arterial stiffening. MMP12 was induced in arterial smooth muscle cells (SMCs) after acute vascular injury. As determined by genome-wide analysis, the magnitude of its gene induction exceeded that of all other MMPs as well as those of the fibrillar collagens and lysyl oxidases, other common regulators of tissue stiffness. A preferential induction of SMC MMP12, without comparable effect on collagen abundance or structure, was also seen during chronic arterial stiffening with age. In both settings, deletion of MMP12 reduced elastin degradation and blocked arterial stiffening as assessed by atomic force microscopy and immunostaining for stiffness-regulated molecular markers. Isolated MMP12-null SMCs sense extracellular stiffness normally, indicating that MMP12 causes arterial stiffening by remodeling the SMC microenvironment rather than affecting the mechanoresponsiveness of the cells themselves. In human aortic samples, MMP12 levels strongly correlate with markers of SMC stiffness. We conclude that MMP12 causes arterial stiffening in mice and suggest that it functions similarly in humans.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Liu
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Bae
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Christopher
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: James
authors.initials: J
authors.lastname: Monslow
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hawthorne
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Paola
authors.initials: P
authors.lastname: Castagnino
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Branchetti
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Damrauer
authors.affiliation: Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian
mesh_terms: D000208:Acute Disease; D000375:Aging / Q000473:pathology; D000818:Animals; D002908:Chronic Disease; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D059289:Vascular Stiffness
chemical_list: D053508:Matrix Metalloproteinase 12