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

Young Kwon Kim, Song Jung Kim, Atsuko Yatani, Yanhong Huang, Germana Castelli, Dorothy E. Vatner, Jing Liu, Qizhi Zhang, Gissela Diaz, Renata Zieba, Jill Thaisz, Alessandra Drusco, Carlo Croce, Junichi Sadoshima, Gianluigi Condorelli, Stephen F. Vatner

Research output: Contribution to journalArticlepeer-review

Abstract

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 Ca2+ 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 (Ica) density was increased in TG compared with WT (-9.0 ± 0.3 versus 7.2 ± 0.3 pA/pF, p <0.01). Sarcoplasmic reticulum Ca2+ 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 Ca2+ channel kinetics more in TG than in WT. Thus, myocytes from mice with overexpressed Akt demonstrated enhanced contractility and relaxation, Fura-2 Ca2+ transients, and Ca2+ 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.

Original languageEnglish
Pages (from-to)47622-47628
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number48
DOIs
Publication statusPublished - Nov 28 2003

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Mechanism of Enhanced Cardiac Function in Mice with Hypertrophy Induced by Overexpressed Akt'. Together they form a unique fingerprint.

Cite this