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) (40μM), the phosphoinositide-3 kinase inhibitor wortmannin (1μM), and the PTEN-resistant PIP3 analog 3-phosphorothioate-PtdIns(3,4,5)P3 (3-PT-PTP, 0.5μM) for 10min. Left ventricular pressure was measured by a Mikro-tip pressure catheter. We then inhibited PTEN in mice by intra-peritoneal injection of VO-OHpic (10μg/kg) 30min before ischemia and then exposed them to 30min of ischemia and 120min 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.
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Lingyun
L
Zu
Zhenyun
Z
Shen
Jacob
J
Wesley
Zheqing P
ZP
Cai
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase