Atorvastatin, administered at the onset of reperfusion, and independent oflipid lowering, protects the myocardiumby up-regulating a pro-survival pathway
Robert M. Bell, MBBS, BSc, PhD* and
Derek M. Yellon, PhD, DSc, Hon FRCP, FACC*,*
* The Hatter Institute for Cardiovascular Studies, Academic and Clinical Cardiology, Division of Medicine, University College Hospitals and Medical School, University College, London, London, United Kingdom
View larger version (20K):
[in a new window]
|
Figure 1 Atorvastatin dose–response curve. Incremental concentrations of atorvastatin resulted in a dose-dependent reduction of infarct size, peaking with 50 µmol/l (**p < 0.001 vs. control). Protection with 100 µmol/l was, however, less than that seen at 50 µmol/l (*p < 0.05 vs. control).
|
|
View larger version (30K):
[in a new window]
|
Figure 2 The Akt phosphorylation time-course. Administration of 25 µmol/l atorvastatin to wild-type hearts at the start of reperfusion after a period of ischemia resulted in a robust and rapid increase in Akt phosphorylation (4.1-fold greater than that seen in control hearts, p < 0.001).
|
|
View larger version (28K):
[in a new window]
|
Figure 3 The eNOS phosphorylation time-course. Administration of 25 µmol/l atorvastatin at the start of reperfusion after a period of ischemia resulted in a similar pattern of phosphorylation of eNOS to that seen with Akt, with a significant 2.8-fold increase over control (p < 0.001).
|
|
View larger version (18K):
[in a new window]
|
Figure 4 The PI3K inhibitor, wortmannin, inhibits the reperfusion salvage seen with 25 µmol/l atorvastatin. Wortmannin administered alone had no impact on infarction (*p < 0.05, atorvastatin group vs. control and wortmannin plus atorvastatin).
|
|
View larger version (16K):
[in a new window]
|
Figure 5 Reperfusion salvage seen with 25 µmol/l atorvastatin is absent in eNOS KO mice. Although atorvastatin results in significant protection in the wild-type hearts (WT), this protection was completely absent in the eNOS KO hearts (*p < 0.001 atorvastatin vs. WT control).
|
|
View larger version (35K):
[in a new window]
|
Figure 6 Akt phosphorylation with atorvastatin after 10 min of reperfusion: the effect of wortmannin and the absence of eNOS. Administration of atorvastatin to wild-type and KO hearts resulted in a robust increase in phosphorylation of Akt, although no cardioprotection is seen in eNOS KO hearts (**p < 0.001 vs. control hearts). The administration of the PI3K inhibitor, wortmannin, significantly reduced Akt phosphorylation compared with both control and atorvastatin-treated hearts ( p < 0.01 vs. both control and atorvastatin groups).
|
|
|
