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Chronic akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy

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Abstract

Aging is often accompanied with geometric and functional changes in the heart, although the underlying mechanisms remain unclear. Recent evidence has described a potential role of Akt and autophagy in aging-associated organ deterioration. This study was to examine the impact of cardiac-specific Akt activation on aging-induced cardiac geometric and functional changes and underlying mechanisms involved. Cardiac geometry, contractile and intracellular Ca2+ properties were evaluated using echocardiography, edge-detection and fura-2 techniques. Level of insulin signaling and autophagy was evaluated by western blot. Our results revealed cardiac hypertrophy (enlarged chamber size, wall thickness, myocyte cross-sectional area), fibrosis, decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca2+ release and clearance in aged (24–26 month-old) mice compared with young (3–4 month-old) mice, the effects of which were accentuated by chronic Akt activation. Aging enhanced Akt and mTOR phosphorylation while reducing that of PTEN, AMPK and ACC with a more pronounced response in Akt transgenic mice. GSK3β phosphorylation and eNOS levels were unaffected by aging or Akt overexpression. Levels of beclin-1, Atg5 and LC3-II-to-LC3-I ratio were decreased in aged hearts, the effect of which with the exception of Atg 5 was exacerbated by Akt overactivation. Levels of p62 were significantly enhanced in aged mice with a more pronounced increase in Akt mice. Neither aging nor Akt altered β-glucuronidase activity and cathepsin B although aging reduced LAMP1 level. In addition, rapamycin reduced aging-induced cardiomyocyte contractile and intracellular Ca2+ dysfunction while Akt activation suppressed autophagy in young but not aged cardiomyocytes. In conclusion, our data suggest that Akt may accentuate aging-induced cardiac geometric and contractile defects through a loss of autophagic regulation.

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Acknowledgments

The authors wish to acknowledge the technical assistance of Ms. Lisa Li from the University of Wyoming. This work was supported in part by NIH/NCRR P20 RR016474.

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Authors and Affiliations

  1. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA

    Yinan Hua, Yingmei Zhang, Asli F. Ceylan-Isik, Jennifer M. Nunn & Jun Ren

  2. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Yingmei Zhang

  3. The Department of Pediatrics, Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, 43205, USA

    Loren E. Wold

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  1. Yinan Hua
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  2. Yingmei Zhang
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Correspondence to Jun Ren.

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Y. Hua and Y. Zhang contributed equally.

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Hua, Y., Zhang, Y., Ceylan-Isik, A.F. et al. Chronic akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy. Basic Res Cardiol 106, 1173–1191 (2011). https://doi.org/10.1007/s00395-011-0222-8

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