Abstract 544: ERK 1/2 is Essential for the Augmentation of Akt and eNOS phosphorylation by Atorvastatin
Background: Several investigators, using in-vitro or isolated heart models, have shown that statins cause a rapid activation of prosurvival kinases, including ERK 1/2, leading to protection against reperfusion injury. However, it has been shown that atorvastatin (ATV) administered at reperfusion does not limit infarct size in endothelial nitric oxide synthase (eNOS) knockout mice, suggesting that the protective effect of ERK is dependent on eNOS. We studied whether ERK is involved in ATV-induced Akt and eNOS phosphorylation.
Methods: Mice received intraperitoneal injection of
ATV (5 mg/kg);
U0126 (an ERK inhibitor, 40 μg/kg);
vehicle alone (n=4 in each group).
Eight hours after injection, mice were euthanized and samples of the left ventricle were assessed for levels of Thr-202/Thr-204 P-ERK, Ser-473 P-Akt, Thr-308 P-Akt, and Ser-1177 P-eNOS by immunoblotting.
Results: ATV increased P-ERK levels (232%). U0126 completely blocked the ATV effect on P-ERK (112%). ATV alone increased myocardial levels of Ser-473 P-Akt (324%) and Thr-308 P-Akt (529%). U0126 alone had no effect on Ser-473 P-Akt and Thr-308 P-Akt levels. U0126 partially blocked the effect of ATV on Ser-473 (180%) and Thr-308 (180%) Akt phosphorylation. ATV alone increased myocardial P-eNOS levels (414%). U0126 alone had no effect; however, it attenuated the ATV-induced increase in P-eNOS levels (160%).
Conclusions: ATV augments ERK phosphorylation. P-ERK facilitates Akt phosphorylation and hence, eNOS phosphorylation. As Akt and eNOS seem to be downstream of ERK, it may explain why statins do not limit infarct size in eNOS knockout mice.