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, Begonã López, Javier Diez, Keith C. WrightRoxanne L. Kovacs, Peng Sheng Chen, Thomas Quertermous, Victoria Smith, Lina Yao, Carsten Tschöpe, Ching Pin Chang

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63 Scopus citations

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.

Original languageEnglish (US)
Article number13710
JournalNature communications
Volume7
DOIs
StatePublished - Dec 14 2016

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Yang, J., Savvatis, K., Kang, J. S., Fan, P., Zhong, H., Schwartz, K., Barry, V., Mikels-Vigdal, A., Karpinski, S., Kornyeyev, D., Adamkewicz, J., Feng, X., Zhou, Q., Shang, C., Kumar, P., Phan, D., Kasner, M., López, B., Diez, J., ... Chang, C. P. (2016). Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nature communications, 7, [13710]. https://doi.org/10.1038/ncomms13710