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 microm/s, p < 0.01). L-type Ca2+ 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.
Highlights
Transgenic mice with cardiac-specific overexpression of active Akt (TG) exhibit hypertrophy and show enhanced left ventricular (LV) function
Up-regulation of SERCA2a expression and enhanced LV myocyte contraction and relaxation in Aktinduced hypertrophy is opposite to the down-regulation of SERCA2a and reduced contractile function observed in many other forms of LV hypertrophy
We found that overexpression of constitutively active Akt analyses of SERCA2a and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is shown
Summary
Transgenic mice with cardiac-specific overexpression of active Akt (TG) exhibit hypertrophy and show enhanced left ventricular (LV) function. The cardioprotection is associated with reduced infarct size as well as preserved function of surviving myocardium [14] Besides these well characterized functions of Akt, transgenic mice with cardiac-specific overexpression of constitutively active Akt have increased base-line contractility, namely an elevated LV1 dP/dtmax [11]. Our results suggest that activation of Akt enhances Ca2ϩ transients and facilitates both contraction and relaxation in isolated cardiac myocytes, which is associated with enhanced Ca2ϩ influx and increased protein levels of SERCA2a. These features indicate a novel function of Akt in the mouse heart
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