Open AccessActivation of Hypoxia‐Inducible Factor‐2 in Adipocytes Results in Pathological Cardiac Hypertrophy
Author(s) -
Lin Qun,
Huang Yan,
Booth Carmen J.,
Haase Volker H.,
Johnson Randall S.,
Celeste Simon M.,
Giordano Frank J.,
Yun Zhong
Publication year - 2013
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000548
Subject(s) - adipose tissue , adipocyte , medicine , proinflammatory cytokine , endocrinology , hypoxia (environmental) , transcription factor , muscle hypertrophy , inflammation , hif1a , hypoxia inducible factors , biology , angiogenesis , gene , chemistry , genetics , organic chemistry , oxygen
Background Obesity can cause structural and functional abnormalities of the heart via complex but largely undefined mechanisms. Emerging evidence has shown that obesity results in reduced oxygen concentrations, or hypoxia, in adipose tissue. We hypothesized that the adipocyte hypoxia‐signaling pathway plays an essential role in the development of obesity‐associated cardiomyopathy. Methods and Results Using a mouse model in which the hypoxia‐inducible factor ( HIF ) pathway is activated by deletion of the von Hippel–Lindau gene specifically in adipocytes, we found that mice with adipocyte–von Hippel–Lindau deletion developed lethal cardiac hypertrophy. HIF activation in adipocytes results in overexpression of key cardiomyopathy‐associated genes in adipose tissue, increased serum levels of several proinflammatory cytokines including interleukin‐1β and monocyte chemotactic protein‐1, and activation of nuclear factor–κB and nuclear factor of activated T cells in the heart. Interestingly, genetic deletion of Hif2a , but not Hif1a , was able to rescue cardiac hypertrophy and abrogate adipose inflammation. Conclusion We have discovered a previously uncharacterized mechanism underlying a critical and direct role of the adipocyte HIF ‐2 transcription factor in the development of adipose inflammation and pathological cardiac hypertrophy.