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Comparative Study
. 2004 Dec;10(12):1384-9.
doi: 10.1038/nm1137. Epub 2004 Nov 21.

Adiponectin-mediated modulation of hypertrophic signals in the heart

Rei Shibata  1 , Noriyuki Ouchi, Masahiro Ito, Shinji Kihara, Ichiro Shiojima, David R Pimentel, Masahiro Kumada, Kaori Sato, Stephan Schiekofer, Koji Ohashi, Tohru Funahashi, Wilson S Colucci, Kenneth Walsh
Affiliations
Comparative Study

Adiponectin-mediated modulation of hypertrophic signals in the heart

Rei Shibata et al. Nat Med. 2004 Dec.

Abstract

Patients with diabetes and other obesity-linked conditions have increased susceptibility to cardiovascular disorders. The adipocytokine adiponectin is decreased in patients with obesity-linked diseases. 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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Figures

Figure 1
Figure 1
Enhanced pressure overload-induced cardiac hypertrophy in APN-KO mice subjected to TAC. (a) Representative pictures of hearts from wild-type (WT) and APN-KO mice at 7 d after sham operation or TAC (left). Representative hematoxylin and eosin-stained cross-sections of left ventricular myocardium from wild-type and APN-KO mice 7 d after sham operation or TAC (right). (b) Representative M-mode echocardiogram for APN-KO and wild-type (WT) mice 7 d after sham operation or TAC. (c) Heart weight/body weight ratio in wild-type (n = 6) and knockout mice (n = 5) 7 d after sham operation or TAC. (d) Histological analysis of heart sections from wild-type and APN-KO mice stained with Masson trichrome (magnification, ×400; bar indicates 50 μm). Quantitative analysis of cardiac myocyte cross-sectional area (n = 200 per section) in wild-type (n = 6) and APN-KO mice (n =5). Results are presented as mean ± s.e.m.
Figure 2
Figure 2
Adenovirus-mediated supplementation of adiponectin protects against the development of cardiac hypertrophy. (a) Oligomeric state of adenovirus-delivered adiponectin in APN-KO mouse (open circle) and endogenous adiponectin in wild-type mouse (closed circles) assessed by gel filtration analysis. The adenoviral vector expressing adiponectin (Ad-APN, 2 × 108 p.f.u. total) was delivered through the jugular vein, and the oligomeric state of adiponectin was analyzed 3 d after Ad-APN injection. (b) Adenovirus-mediated supplementation of adiponectin in APN-KO and wild-type (WT) mice attenuated cardiac hypertrophy in response to TAC as shown by echocardiography. Adenoviral vectors expressing adiponectin (Ad-APN, 2 × 108 p.f.u. total, n = 3) or β-galactosidase (control, n = 3) were delivered intravenously through the jugular vein 3 d before TAC surgery. Left ventricular wall thickness (IVS and LVPW) was determined at 3 d after TAC. (c) Heart weight/body weight ratio and cardiac myocyte cross-sectional area in wild-type (n = 5) and knockout mice (n = 3) treated with Ad-APN or Ad-βgal (control) were determined at 7 d after sham operation or TAC. (d) Decreased survival of APN-KO mice (closed squares) after TAC (n = 20; *P < 0.05, **P < 0.01) in comparison with wild-type mice (closed circles) after TAC (n = 20). Adenovirus-mediated supplementation of adiponectin in APN-KO (n = 9) (open circles) improved survival to a level that is comparable to that of wild-type mice. (e) Adenovirus-mediated supplementation of adiponectin in diabetic db/db mice attenuated cardiac hypertrophy in response to TAC as shown by echocardiography. Ad-APN (2 × 108 p.f.u. total, n = 4) or β-galactosidase (control, n = 4) were delivered intravenously through the jugular vein 3 d before TAC surgery. Wall thickness (IVS and LVPW) was determined at 3 d after TAC surgery or sham operation. (f) APN-KO mice showed an increased cardiac hypertrophy following AngII infusion relative to wild-type mice (n = 4). Adenovirus-mediated supplementation of adiponectin (2 × 108 p.f.u.) in APN-KO (n = 4) and wild-type (n = 4) mice attenuated AngII-induced cardiac hypertrophy. Wall thickness (IVS and LVPW) was determined after 14 d of AngII infusion. Results are presented as mean ± s.e.m.
Figure 3
Figure 3
Adiponectin inhibits the hypertrophic response to αAR stimulation or pressure overload. (a) Representative example of immunostaining of sarcomeric F-actin with rhodamine phalloidin in rat cardiac myocytes. Cells were pretreated with adiponectin (30 μg/ml) or vehicle for 30 min, Pro (2 μM) for an additional 30 min, followed by the addition of norepinephrine (NE) for 48 h. (b) Quantitative analysis of cell surface area measured by semi-automatic computer-assisted planimetry (Bioquant) from two-dimensional images of 100 cells selected at random (left) and protein synthesis measured by [3H]-leucine incorporation (right). (c) The phosphorylation (P-) of ERK in heart tissues from wild-type and APN-KO mice at 7 d after sham operation or TAC. (d) Effect of adiponectin on the phosphorylation of ERK in response to αAR-stimulation in cultured rat cardiac myocytes. Cells were pretreated with adiponectin (30 μg/ml) or vehicle for 30 min, 2 μM Pro for an additional 30 min and then stimulated with or without 1 μM norepinephrine (NE) for the indicated length of time. (e) Effects of three different oligomeric forms of adiponectin on the phosphorylation of ERK in response to αAR-stimulation in cultured rat cardiac myocytes. Cells were pretreated with each form of adiponectin (5 μg/ml) or vehicle for 30 min, 2 μM Pro for an additional 30 min and then stimulated with 1 μM NE for 5 min. Relative phosphorylation levels of ERK were quantified using the US National Institutes of Health image program. Immunoblots were normalized to total loaded protein. Results are presented as mean ± s.d. (n = 3–6). *P < 0.05 versus wild-type. **P < 0.05 versus control.
Figure 4
Figure 4
Adiponectin inhibition αAR-stimulated myocyte hypertrophy is mediated through AMPK signaling. (a) Time-dependent changes in the phosphorylation of AMPK in rat cultured cardiac myocytes after adiponectin treatment (30 μg/ml). (b) Effects of three different oligomeric forms of adiponectin (5 μg/ml) on the phosphorylation of AMPK. (c) The phosphorylation of AMPK in myocardium from wild-type (WT) and APN-KO mice at 7 d after sham operation or TAC. (d) Ad-dnAMPK reversed adiponectin stimulation of AMPK and ACC phosphorylation. Rat cardiac myocytes were transduced with c-Myc-tagged Ad-dnAMPK or Ad-βgal (control) at a multiplicity of infection of 50 for 24 h in serum-starved media. Cells were treated with adiponectin (30 μg/ml) for the indicated lengths of time. (e) Contribution of AMPK signaling to the inhibitory effect of adiponectin on αAR-stimulated myocyte hypertrophy. After 24-h transduction of rat cardiac myocytes with Ad-dnAMPK or Ad-βgal (control), cells were pretreated with adiponectin (30 μg/ml) or vehicle for 30 min and then treated with 2 μM Pro for 30 min and stimulated with or without 1 μM norepinephrine (NE) for 48 h. Quantitative analysis of cell surface area was performed in 100 randomly selected cells (left) or 3H-leucine incorporation into protein (right). (f) Effect of Ad-dnAMPK on adiponectin inhibition of NE/Pro-induced ERK phosphorylation. Cells were treated as in e and then stimulated with or without 1 μM norepinephrine (NE) for the indicated lengths of time. Relative phosphorylation levels of AMPK and ERK were quantified using the US National Institutes of Health image program. Immunoblots were normalized to total loaded protein. Results are presented as mean ± s.d. (n = 3–5). *P < 0.05 versus wild-type. **P < 0.05 versus control.
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