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 Takeda, Kimi Araki, Ichiro Manabe, Keiichi Fukuda, Kinya Otsu, Jun Wada, Toyoaki Murohara, Satoshi Mohri, Jun K. Yamashita, Motoaki Sano and Yuichi Oike ()
Additional contact information
Zhe Tian: Graduate School of Medical Sciences, Kumamoto University
Keishi Miyata: Graduate School of Medical Sciences, Kumamoto University
Tsuyoshi Kadomatsu: Graduate School of Medical Sciences, Kumamoto University
Haruki Horiguchi: Graduate School of Medical Sciences, Kumamoto University
Hiroyuki Fukushima: Center for iPS Cell Research and Application (CiRA), Kyoto University
Shugo Tohyama: School of Medicine, Keio University
Yoshihiro Ujihara: Kawasaki Medical School
Takahiro Okumura: Nagoya University Graduate school of Medicine
Satoshi Yamaguchi: Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Jiabin Zhao: Graduate School of Medical Sciences, Kumamoto University
Motoyoshi Endo: Graduate School of Medical Sciences, Kumamoto University
Jun Morinaga: Graduate School of Medical Sciences, Kumamoto University
Michio Sato: Graduate School of Medical Sciences, Kumamoto University
Taichi Sugizaki: Graduate School of Medical Sciences, Kumamoto University
Shunshun Zhu: Graduate School of Medical Sciences, Kumamoto University
Kazutoyo Terada: Graduate School of Medical Sciences, Kumamoto University
Hisashi Sakaguchi: Graduate School of Medical Sciences, Kumamoto University
Yoshihiro Komohara: Graduate School of Medical Sciences, Kumamoto University
Motohiro Takeya: Graduate School of Medical Sciences, Kumamoto University
Naoki Takeda: Institute of Resource Developmental and Analysis, Kumamoto University
Kimi Araki: Institute of Resource Developmental and Analysis, Kumamoto University
Ichiro Manabe: Graduate School of Medicine, Chiba University
Keiichi Fukuda: School of Medicine, Keio University
Kinya Otsu: King’s College London British Heart Foundation Centre of Research Excellence
Jun Wada: Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Toyoaki Murohara: Nagoya University Graduate school of Medicine
Satoshi Mohri: Kawasaki Medical School
Jun K. Yamashita: Center for iPS Cell Research and Application (CiRA), Kyoto University
Motoaki Sano: School of Medicine, Keio University
Yuichi Oike: Graduate School of Medical Sciences, Kumamoto University

Nature Communications, 2016, vol. 7, issue 1, 1-19

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13016

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