Research article

Forced expression of the cell cycle inhibitor p57^Kip2 in cardiomyocytes attenuates ischemia-reperfusion injury in the mouse heart

Sheila A Haley¹ , Ting Zhao^2,4 , Lijun Zou^3,4 , Jan E Klysik¹ , James F Padbury^2,4 and Lazaros K Kochilas^3,4

¹Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA

²Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Women and Infants Hospital, Providence, RI 02903, USA

³Department of Pediatrics, Division of Pediatric Cardiology, Rhode Island Hospital, Providence, RI 02903, USA

⁴Department of Pediatrics, Warren Alpert School of Medicine, Brown University, Providence, RI 02912, USA

author email corresponding author email

BMC Physiology 2008, 8:4doi:10.1186/1472-6793-8-4

Published:	29 February 2008

Abstract

Background

Myocardial hypoxic-ischemic injury is the cause of significant morbidity and mortality worldwide. The cardiomyocyte response to hypoxic-ischemic injury is known to include changes in cell cycle regulators. The cyclin-dependent kinase inhibitor p57^Kip2 is involved in cell cycle control, differentiation, stress signaling and apoptosis. In contrast to other cyclin-dependent kinase inhibitors, p57^Kip2 expression diminishes during postnatal life and is reactivated in the adult heart under conditions of cardiac stress. Overexpression of p57^Kip2 has been previously shown to prevent apoptotic cell death in vitro by inhibiting stress-activated kinases. Therefore, we hypothesized that p57^Kip2 has a protective role in cardiomyocytes under hypoxic conditions. To investigate this hypothesis, we created a transgenic mouse (R26loxpTA-p57^k/+) that expresses p57^Kip2 specifically in cardiac tissue under the ventricular cardiomyocyte promoter Mlc2v.

Results

Transgenic mice with cardiac specific overexpression of p57^Kip2 are viable, fertile and normally active and their hearts are morphologically indistinguishable from the control hearts and have similar heart weight/body weight ratio. The baseline functional parameters, including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LVdp/dt_max, heart rate (HR) and rate pressure product (RPR) were not significantly different between the different groups as assessed by the Langendorff perfused heart preparation. However, after subjecting the heart ex vivo to 30 minutes of ischemia-reperfusion injury, the p57^Kip2 overexpressing hearts demonstrated preserved cardiac function compared to control mice with higher left ventricular developed pressure (63 ± 15 vs 30 ± 6 mmHg, p = 0.05), rate pressure product (22.8 ± 4.86 vs 10.4 ± 2.1 × 10³bpm × mmHg, p < 0.05) and coronary flow (3.5 ± 0.5 vs 2.38 ± 0.24 ml/min, p <0.05).

Conclusion

These data suggest that forced cardiac expression of p57^Kip2 does not affect myocardial growth, differentiation and baseline function but attenuates injury from ischemia-reperfusion in the adult mouse heart.