Mechanism of Enhanced Cardiac Function in Mice with Hypertrophy Induced by Overexpressed Akt

• Published in: The Journal of biological chemistry Vol. 278; no. 48; pp. 47622 - 47628
• Main Authors: Kim, Young-Kwon, Kim, Song-Jung, Yatani, Atsuko, Huang, Yanhong, Castelli, Germana, Vatner, Dorothy E, Liu, Jing, Zhang, Qizhi, Diaz, Gissela, Zieba, Renata, Thaisz, Jill, Drusco, Alessandra, Croce, Carlo, Sadoshima, Junichi, Condorelli, Gianluigi, Vatner, Stephen F
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 28-11-2003
• Subjects: Adenoviridae - genetics; Alkaline Phosphatase - chemistry; Animals; Blotting, Western; Body Weight; Calcium - metabolism; Calcium-Transporting ATPases - chemistry; Calsequestrin - chemistry; Dose-Response Relationship, Drug; Down-Regulation; Echocardiography; Electrophysiology; Enzyme Inhibitors - pharmacology; Fura-2 - pharmacology; Heart Ventricles - pathology; Hypertrophy; Inhibitory Concentration 50; Kinetics; Lysophospholipase - chemistry; Mice; Mice, Transgenic; Muscle Cells - metabolism; Organ Size; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Reverse Transcriptase Polymerase Chain Reaction; Ryanodine - pharmacology; Ryanodine Receptor Calcium Release Channel - chemistry; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Thapsigargin - chemistry; Thapsigargin - pharmacology; Time Factors; Transfection; Transgenes; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M305909200

Transgenic mice with cardiac-specific overexpression of active Akt (TG) not only exhibit hypertrophy but also show enhanced
left ventricular (LV) function. In 3–4-month-old TG, heart/body weight was increased by 60% and LV ejection fraction was elevated
(84 ± 2%, p < 0.01) compared with nontransgenic littermates (wild type (WT)) (73 ± 1%). An increase in isolated ventricular myocyte contractile
function (% contraction) in TG compared with WT (6.1 ± 0.2 versus 3.5 ± 0.2%, p < 0.01) was associated with increased Fura-2 Ca 2+ transients (396 ± 50 versus 250 ± 24 nmol/liter, p < 0.05). The rate of relaxation (+dL/dt) was also enhanced in TG (214 ± 15 versus 98 ± 18 μm/s, p < 0.01). L-type Ca 2+ current ( I Ca ) density was increased in TG compared with WT (-9.0 ± 0.3 versus 7.2 ± 0.3 pA/pF, p < 0.01). Sarcoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) protein levels were increased ( p < 0.05) by 6.6-fold in TG, which could be recapitulated in vitro by adenovirus-mediated overexpression of Akt in cultured adult ventricular myocytes. Conversely, inhibiting SERCA with either
ryanodine or thapsigargin affected myocyte contraction and relaxation and Ca 2+ channel kinetics more in TG than in WT. Thus, myocytes from mice with overexpressed Akt demonstrated enhanced contractility
and relaxation, Fura-2 Ca 2+ transients, and Ca 2+ channel currents. Furthermore, increased protein expression of SERCA2a plays an important role in mediating enhanced LV function
by Akt. Up-regulation of SERCA2a expression and enhanced LV myocyte contraction and relaxation in Akt-induced hypertrophy
is opposite to the down-regulation of SERCA2a and reduced contractile function observed in many other forms of LV hypertrophy.