Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment

Jin Yang, Konstantinos Savvatis, Jong Seok Kang, Peidong Fan, Hongyan Zhong, Karen Schwartz, Vivian Barry, Amanda Mikels-Vigdal, Serge Karpinski, Dmytro Kornyeyev, Joanne Adamkewicz, Xuhui Feng, Qiong Zhou, Ching Shang, Praveen Kumar, Dillon Phan, Mario Kasner, Begoña López, Javier Diez, Keith C. Wright, Roxanne L. Kovacs, Peng-Sheng Chen, Thomas Quertermous, Victoria Smith, Lina Yao (), Carsten Tschöpe and Ching-Pin Chang ()
Additional contact information
Jin Yang: Indiana University School of Medicine
Konstantinos Savvatis: Campus Virchow-Klinikum, Charité University Medicine Berlin
Jong Seok Kang: Gilead Sciences Inc.
Peidong Fan: Gilead Sciences Inc.
Hongyan Zhong: Gilead Sciences Inc.
Karen Schwartz: Gilead Sciences Inc.
Vivian Barry: Gilead Sciences Inc.
Amanda Mikels-Vigdal: Gilead Sciences Inc.
Serge Karpinski: Gilead Sciences Inc.
Dmytro Kornyeyev: Gilead Sciences Inc.
Joanne Adamkewicz: Gilead Sciences Inc.
Xuhui Feng: Indiana University School of Medicine
Qiong Zhou: Indiana University School of Medicine
Ching Shang: Indiana University School of Medicine
Praveen Kumar: Gilead Sciences Inc.
Dillon Phan: Gilead Sciences Inc.
Mario Kasner: Campus Virchow-Klinikum, Charité University Medicine Berlin
Begoña López: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University Clinic, University of Navarra
Javier Diez: Program of Cardiovascular Diseases, Centre for Applied Medical Research, University Clinic, University of Navarra
Keith C. Wright: Indiana University School of Medicine
Roxanne L. Kovacs: Indiana University School of Medicine
Peng-Sheng Chen: Indiana University School of Medicine
Thomas Quertermous: Stanford University
Victoria Smith: Gilead Sciences Inc.
Lina Yao: Gilead Sciences Inc.
Carsten Tschöpe: Campus Virchow-Klinikum, Charité University Medicine Berlin
Ching-Pin Chang: Indiana University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13710

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