PTEN inhibitors cause a negative inotropic and chronotropic effect in mice

Inactivation of phosphatase and tensin homologue deleted on chromosome ten (PTEN) decreases cardiac contractility under basal conditions and induces cardioprotection against ischemia-reperfusion injury However the pharmacological effect of PTEN inhibitors on cardiac contractility has not been studied before In the present study we investigated the hypothesis that PTEN Inhibition decreases cardiac contractility in mice We first exposed Isolated mouse hearts to the PTEN inhibitor bpV(phen) (40 mu M) the phosphoinositide-3 kinase inhibitor wortmannin (1 mu M) and the PTEN resistant PIP3 analog 3-phosphorothioate-PtdIns(3 4 5)P3 (3-PT PIP 0 5 mu M) for 10 min Left ventricular pressure was measured by a Mikro-tip pressure catheter We then inhibited PTEN in mice by intra peritoneal injection of VO OHpic (10 mu g/kg) 30 mm before ischemia and then exposed them to 30 min of ischemia and 120 mm of reperfusion At the end of the experiments hearts were isolated for measurement of myocardial infarct size by 1 5% triphenyltetrazolium chloride Left ventricular systolic pressure and heart rate were significantly decreased by bpV(phen) Consistent with the result the maximal rate of left ventricular pressure increase or decrease was significantly decreased by bpV (phen) 3 PT-PIP3 mimicked the effect of bpV(phen) and the opposite effect on cardiac contractility was seen with wortmannin Moreover inhibition of PTEN in vivo by VO-OHpic decreased left ventricular systolic pressure and heart rate before ischemia but resulted in an increase in cardiac functional recovery and a decrease in myocardial infarct size after ischemia-reperfusion In conclusion PTEN inhibition causes a negative inotropic and chronotropic effect while inducing cardioprotection against ischemia-reperfusion injury (C) 2010 Elsevier B V All rights reserved