ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism.
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.
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.|Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Zhe
Z
Tian
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.|Department of Immunology, Allergy, and Vascular Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Keishi
K
Miyata
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Tsuyoshi
T
Kadomatsu
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.|Institute of Resource Developmental and Analysis, Kumamoto University, Kumamoto 860-8111, Japan.
Haruki
H
Horiguchi
Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
Hiroyuki
H
Fukushima
Department of Cardiovascular Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Shugo
S
Tohyama
First Department of Physiology, Kawasaki Medical School, Okayama 701-092, Japan.
Yoshihiro
Y
Ujihara
Department of Cardiology, Nagoya University Graduate school of Medicine, Nagoya 466-8550, Japan.
Takahiro
T
Okumura
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Satoshi
S
Yamaguchi
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Jiabin
J
Zhao
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Motoyoshi
M
Endo
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Jun
J
Morinaga
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Michio
M
Sato
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Taichi
T
Sugizaki
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Shunshun
S
Zhu
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Kazutoyo
K
Terada
Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Hisashi
H
Sakaguchi
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Yoshihiro
Y
Komohara
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Motohiro
M
Takeya
Institute of Resource Developmental and Analysis, Kumamoto University, Kumamoto 860-8111, Japan.
Naoki
N
Takeda
Institute of Resource Developmental and Analysis, Kumamoto University, Kumamoto 860-8111, Japan.
Kimi
K
Araki
Department of Aging Research, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Ichiro
I
Manabe
Department of Cardiovascular Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Keiichi
http://orcid.org/0000-0003-1413-0482
K
Fukuda
Cardiovascular Division, King's College London British Heart Foundation Centre of Research Excellence, London SE5 9NU, UK.
Kinya
K
Otsu
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Jun
J
Wada
Department of Cardiology, Nagoya University Graduate school of Medicine, Nagoya 466-8550, Japan.
Toyoaki
T
Murohara
First Department of Physiology, Kawasaki Medical School, Okayama 701-092, Japan.
Satoshi
S
Mohri
Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
Jun K
JK
Yamashita
Department of Cardiovascular Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Motoaki
M
Sano
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Yuichi
Y
Oike
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