T-cadherin is critical for adiponectin-mediated cardioprotection in mice

The circulating, adipocyte-secreted hormone adiponectin (APN) exerts protective effects on the heart under stress conditions. The receptors binding APN to cardiac tissue, however, have remained elusive. Here, we report that the glycosyl phosphatidylinositol–anchored cell surface glycoprotein T-cadhe...

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Bibliographic Details
Published in:The Journal of clinical investigation 2010-12, Vol.120 (12), p.4342-4352
Main Authors: Denzel, Martin S, Scimia, Maria-Cecilia, Zumstein, Philine M, Walsh, Kenneth, Ruiz-Lozano, Pilar, Ranscht, Barbara
Format: Article
Language:English
Subjects:
Adipocytes
Adiponectin - deficiency
Adiponectin - genetics
Adiponectin - physiology
AMP-Activated Protein Kinases - metabolism
Animals
Base Sequence
Biomedical research
Cadherins
Cadherins - deficiency
Cadherins - genetics
Cadherins - physiology
Cardiomegaly - pathology
Cardiomegaly - physiopathology
Cardiomegaly - prevention & control
Cardiomyocytes
Cardiotonic Agents - metabolism
Cardiovascular disease
Clinical medicine
DNA Primers - genetics
Glycoproteins
Heart Diseases - pathology
Heart Diseases - physiopathology
Heart Diseases - prevention & control
Heart enlargement
Heart failure
Hyperlipidemia
Hypertension
Ischemia
Lipids
Localization
Male
Metabolic syndrome
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardial Reperfusion Injury - pathology
Myocardial Reperfusion Injury - physiopathology
Myocardial Reperfusion Injury - prevention & control
Myocardium - metabolism
Myocytes, Cardiac - metabolism
Phosphorylation
Physiology
Prevention
Properties
Risk factors
Signal Transduction
Stress, Physiological
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Summary:The circulating, adipocyte-secreted hormone adiponectin (APN) exerts protective effects on the heart under stress conditions. The receptors binding APN to cardiac tissue, however, have remained elusive. Here, we report that the glycosyl phosphatidylinositol–anchored cell surface glycoprotein T-cadherin (encoded by Cdh13) protects against cardiac stress through its association with APN in mice. We observed extensive colocalization of T-cadherin and APN on cardiomyocytes in vivo. In T-cadherin-deficient mice, APN failed to associate with cardiac tissue, and its levels dramatically increased in the circulation. Pressure overload stress resulted in exacerbated cardiac hypertrophy in T-cadherin-null mice and paralleled corresponding defects in mice lacking APN. During ischemia-reperfusion injury, the absence of T-cadherin increased infarct size similar to that in APN-null mice. Myocardial AMPK is a major downstream protective signaling target of APN. In both cardiac hypertrophy and ischemia-reperfusion models, T-cadherin was necessary for APN-dependent AMPK phosphorylation. In APN-null mice, recombinant adenovirus-expressed APN reduced exaggerated hypertrophy and infarct size and restored AMPK phosphorylation as previously reported. In contrast, rescue was ineffective in mice lacking T-cadherin in addition to APN. These data suggest that T-cadherin protects from stress-induced pathological cardiac remodeling by binding APN and activating its cardioprotective functions.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI43464