ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism

Zhe Tian, Keishi Miyata, Tsuyoshi Kadomatsu, Haruki Horiguchi, Hiroyuki Fukushima, Shugo Tohyama, Yoshihiro Ujihara, Takahiro Okumura, Satoshi Yamaguchi, Jiabin Zhao, Motoyoshi Endo, Jun Morinaga, Michio Sato, Taichi Sugizaki, Shunshun Zhu, Kazutoyo Terada, Hisashi Sakaguchi, Yoshihiro Komohara, Motohiro Takeya, Naoki TakedaKimi Araki, Ichiro Manabe, Keiichi Fukuda, Kinya Otsu, Jun Wada, Toyoaki Murohara, Satoshi Mohri, Jun K. Yamashita, Motoaki Sano, Yuichi Oike

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure.

Original languageEnglish
Article number13016
JournalNature communications
Volume7
DOIs
Publication statusPublished - Sep 28 2016

ASJC Scopus subject areas

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

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    Tian, Z., Miyata, K., Kadomatsu, T., Horiguchi, H., Fukushima, H., Tohyama, S., Ujihara, Y., Okumura, T., Yamaguchi, S., Zhao, J., Endo, M., Morinaga, J., Sato, M., Sugizaki, T., Zhu, S., Terada, K., Sakaguchi, H., Komohara, Y., Takeya, M., ... Oike, Y. (2016). ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism. Nature communications, 7, [13016]. https://doi.org/10.1038/ncomms13016