title: Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment.
abstract: Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Campus Virchow-Klinikum, Charité University Medicine Berlin, 13353 Berlin, Germany.|Berlin-Brandenburg Centre for Regenerative Therapies, Charité University Medicine Berlin, 10117 Berlin, Germany.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Savvatis
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Kang
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Peidong
authors.initials: P
authors.lastname: Fan
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Schwartz
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Barry
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mikels-Vigdal
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Karpinski
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Kornyeyev
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Adamkewicz
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Feng
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Ching
authors.initials: C
authors.lastname: Shang
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Dillon
authors.initials: D
authors.lastname: Phan
authors.affiliation: Department of Cardiology, Campus Virchow-Klinikum, Charité University Medicine Berlin, 13353 Berlin, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Kasner
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, Department of Cardiology and Cardiac Surgery, University Clinic, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.affiliation: Program of Cardiovascular Diseases, Centre for Applied Medical Research, Department of Cardiology and Cardiac Surgery, University Clinic, University of Navarra, 31008 Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Diez
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Keith C
authors.initials: KC
authors.lastname: Wright
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Roxanne L
authors.initials: RL
authors.lastname: Kovacs
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Cardiology, Campus Virchow-Klinikum, Charité University Medicine Berlin, 13353 Berlin, Germany.|Berlin-Brandenburg Centre for Regenerative Therapies, Charité University Medicine Berlin, 10117 Berlin, Germany.|DZHK, German Centre for Cardiovascular Research, Partner Site Berlin - Charité, 13347 Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.|Gilead Sciences Inc., Foster City, California 94404, USA.
authors.forename: Ching-Pin
authors.initials: CP
authors.lastname: Chang
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D005355:Fibrosis / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D013312:Stress, Physiological
chemical_list: D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; C485601:Loxl2 protein, mouse