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Adiponectin-mediated modulation of hypertrophic signals in the heart

Abstract

Patients with diabetes and other obesity-linked conditions have increased susceptibility to cardiovascular disorders1. The adipocytokine adiponectin is decreased in patients with obesity-linked diseases2. Here, we found that pressure overload in adiponectin-deficient mice resulted in enhanced concentric cardiac hypertrophy and increased mortality that was associated with increased extracellular signal-regulated kinase (ERK) and diminished AMP-activated protein kinase (AMPK) signaling in the myocardium. Adenovirus-mediated supplemention of adiponectin attenuated cardiac hypertrophy in response to pressure overload in adiponectin-deficient, wild-type and diabetic db/db mice. In cultures of cardiac myocytes, adiponectin activated AMPK and inhibited agonist-stimulated hypertrophy and ERK activation. Transduction with a dominant-negative form of AMPK reversed these effects, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium through activation of AMPK signaling. Adiponectin may have utility for the treatment of hypertrophic cardiomyopathy associated with diabetes and other obesity-related diseases.

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Figure 1: Enhanced pressure overload–induced cardiac hypertrophy in APN-KO mice subjected to TAC.
Figure 2: Adenovirus-mediated supplementation of adiponectin protects against the development of cardiac hypertrophy.
Figure 3: Adiponectin inhibits the hypertrophic response to αAR stimulation or pressure overload.
Figure 4: Adiponectin inhibition αAR-stimulated myocyte hypertrophy is mediated through AMPK signaling.

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Acknowledgements

We acknowledge the technical assistance of S. Tanaka and A. Bialik. This work was supported by US National Institutes of Health (NIH) grants HL66957, AR40197, AG15052 and AG17241 to K. Walsh, HL61639 and HL20612 to W.S. Colucci, NIH Cardiovascular Scientist Training Grant HL07224 to D.R. Pimentel; and grants from the Japanese Ministry of Education and the Japan Society for Promotion of Science-Research for the Future Program. R. Shibata, N. Ouchi and M. Ito were supported by grants from the Uehara Memorial Foundation.

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Correspondence to Kenneth Walsh.

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Supplementary Table 1

Body weight, hemodynamic and echocardiographic measurements in wild-type and APN-KO mice at 7 days post-surgery. (PDF 289 kb)

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Shibata, R., Ouchi, N., Ito, M. et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med 10, 1384–1389 (2004). https://doi.org/10.1038/nm1137

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