Submitted on December 12, 2006
Accepted on February 20, 2007
The cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation
Aliaksandr A Bulhak1*, Joy Roy2, Ulf Hedin2, Per-Ove Sjoquist3, and John Pernow3
1 Department of Medicine, Cardiology Unit, Karolinska Institute, Stockholm, Sweden
2 Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Stockholm, Sweden
3 Stockholm, Sweden; Department of Medicine, Cardiology Unit, Karolinska Institute, Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: aliaksandr.bulhak{at}ki.se.
Background: HMG-CoA reductase inhibitors (statins) protect the myocardium against ischemia/reperfusion injury via a mechanism unrelated to cholesterol-lowering. Statins may inhibit isoprenylation and thereby prevent activation of proteins such as RhoA. We hypothesized that statins protect the myocardium against ischemia/reperfusion injury via mechanism involving inhibition of geranylgeranyl pyrophosphate synthesis and translocation of RhoA to the plasma membrane.
Methods: Sprague-Dawley rats were given either the HMG-CoA reductase inhibitor rosuvastatin, geranylgeranyl pyrophosphate dissolved in methanol, the combination of rosuvastatin and geranylgeranyl pyrophosphate, rosuvastatin and methanol, or distilled water (control) by intraperitoneal injection for 48 h before ischemia/reperfusion. Animals were anesthetized and either subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion whereat infarct size was determined, or the expression of RhoA protein was determined in cytosolic and membrane fractions of non-ishemic myocardium.
Results: There were no significant differences in hemodynamics between the control group and the other groups before ischemia or during ischemia and reperfusion. The infarct size was 80±3% of the area at risk in the control group. Rosuvastatin reduced infarct size to 64±2% (p<0.001 vs. control). Addition of geranylgeranyl pyrophosphate (77±2%, p<0.01 vs. rosuvastatin) but not methanol (65±2% in the, ns vs. rosuvastatin) abolished the cardioprotective effect of rosuvastatin. Geranylgeranyl pyrophosphate alone did not affect infarct size per se (84±2%). Rosuvastatin increased the cytosol/membrane ratio of RhoA protein in the myocardium (p<0.05 vs. control). These changes were abolished by addition of geranylgeranyl pyrophosphate.
Conclusions: The cardioprotection and the increase of RhoA cytosol/membrane ratio induced by rosuvastatin in vivo are blocked by geranylgeranyl pyrophosphate. The inhibition of geranylgeranyl pyrophosphate formation and subsequent modulation of cytosol/membrane-bound RhoA are of importance for the protective effect of statins against myocardial ischemia/reperfusion injury.
