Propofol attenuates apoptosis induced by angiotensin II via the PI3-kinase/Akt pathway in neonatal rat cardiomyocytes

Abstract

Background and Goal of Study: Propofol protects cells against oxidative injury in several organs, but the mechanism by which it exerts the cardioprotective effect is not well established. Angiotensin II (Ang II) can induce cardiomyocy te apoptosis which has an important role in the transition from compensatory cardiac remodeling to heart failure. In the present study, we evaluated the effects of propofol on Ang II-mediated cardiomyocyte apoptosis.

Materials and Methods: Cultured cardiomyocytes from neonatal rats were stimulated with Ang II. Apoptosis was evaluated by measuring caspase 3 activity and by TdT-mediated dUTP nick-end labeling (TUNEL) method. To further investigate the underlying mechanisms, the quantity of cleaved caspase-3, cytosol cytochrome c release, BcL-xL expression, and ROS generation were examined. The effects of propofol on Akt phosphorylation and the involvement of PI3K/Akt pathway also assessed.

Results and Discussion: It was found that incubation with Ang II (0.1 μM) for 48 h increased cardiomyocyte apoptosis. Administration of propofol (3-10 mM) significantly decreased this Ang II-induced apoptosis.

These results suggest that propofol abates cardiomyocytes from Ang II-induced apoptosis possibly via reduced the quantity of cleaved caspase-3, and cytosol cytochrome c, and increased BcL-xL expression, and inhibiting the increased ROS generation. In addition, propofol was found to increase the Akt phosphorylation in cardiomyocytes. The siRNA transfection for Akt significantly reduced propofol-induced Akt phosphorylation and propofol's protective effect. Pretreatment with the PI3K inhibitors wortmannin and LY294002 inhibited serine phosphorylation of Akt in dose-dependent manners. These findings indicate that propofol induces Akt phosphorylation via the PI3K/Akt pathway.

Our data provide the first evidence that the anti-apoptotic effect of propofol may be an important underlying mechanism accounting for its cardioprotectant action.

Conclusion(s): Propofol might potentially be developed to treat heart failure or other apoptosis-related heart diseases if further studies were performed to define and clarify rationale for its clinical use.

Acknowledgements: Supported by grant No. NSC-96-2320-B-039-009-MY3 and NSC-99-2320-B-039-027-MY2 from the National Science Council, Taiwan (to KL Wong), and grant No. DMR-99-097 from the China Medical University, Taichung, Taiwan (to KL Wong)