title: Apolipoprotein E3 Inhibits Rho to Regulate the Mechanosensitive Expression of Cox2.
abstract: Apolipoprotein E3 (apoE3) is thought to protect against atherosclerosis by enhancing reverse cholesterol transport. However, apoE3 also has cholesterol-independent effects that contribute to its anti-atherogenic properties. These include altering extracellular matrix protein synthesis and inhibiting vascular smooth muscle cell proliferation. Both of these cholesterol-independent effects result from an apoE3-mediated induction of cyclooxygenase-2 (Cox2). Nevertheless, how apoE3 regulates Cox2 remains unknown. Here, we show that apoE3 inhibits the activation of Rho, which reduces the formation of actin stress fibers and focal adhesions and results in cellular softening. Inhibition of Rho-Rho kinase signaling or direct cellular softening recapitulates the effect of apoE3 on Cox2 expression while a constitutively active Rho mutant overrides the apoE3 effect on both intracellular stiffness and Cox2. Thus, our results describe a previously unidentified mechanism by which an atheroprotective apolipoprotein uses Rho to control cellular mechanics and Cox2.
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Bernadette Y
authors.initials: BY
authors.lastname: Hsu
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Bae
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Keeley L
authors.initials: KL
authors.lastname: Mui
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Liu
authors.affiliation: Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian
mesh_terms: D000199:Actins / Q000378:metabolism; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D040542:Mechanotransduction, Cellular; D018625:Microscopy, Atomic Force; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D051419:Paxillin / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D022502:Stress Fibers / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000199:Actins; D053318:Apolipoprotein E3; D051419:Paxillin; D011994:Recombinant Proteins; D006160:Guanosine Triphosphate; D051546:Cyclooxygenase 2; D054460:rho-Associated Kinases