| BackgroundCoronary atherosclerotic heart disease, especially acute myocardial infarction, is a major cause of death worldwide. Reperfusion therapy, including intervention, coronary artery bypass grafting (CABG) and thrombolysis, is the main treatment for myocardial infarction. However, the sudden increase in blood flow that results from successful treatment causes reperfusion injury, and ischemia/reperfusion (I/R) injury is a major cause of death in acute myocardial infarction patients after reperfusion. Ischemic preconditioning (IPC) and ischemic postconditioning (I-PostC) induce endogenous protective mechanisms that attenuate reperfusion injury. But the repeated transient ischemia/reperfusion (I/R) cycles used in pre-and postconditioning may cause injury, a drawback that limits the use of these techniques in clinical practice. Recently, attempts have been made to substitute drug administration for the transient ischemia/reperfusion cycles in used in ischemic postconditioning. Pharmacological postconditioning (PPC) avoids the potential injury induced by ischemic post-conditioning and is easier to perform, and therefore has better clinical potential than ischemic postconditioning. Statins (3-hydroxy-3-methylglutaryl coenzyme A, HMG-CoA reductase inhibitors), a drug class used in primary and secondary prevention of coronary heart disease, exert pleiotropic effects that are independent of the lipid-lowering effect. Although it is known that PPC with statins attenuates myocardial I/R injury, the mechanisms underlying this cardioprotection are incompletely understood. One mechanism through which I/R causes injury is induction of myocardial endoplasmic reticulum (ER) stress. Inhibition of ER stress-related apoptosis has become a target in treatment of myocardial I/R injury. As shown in our previous study, ischemic post-conditioning inhibits ER stress-related apoptosis. In the present study, we examined whether atorvastatin, when used for pharmacological post-conditioning, attenuated myocardial I/R injury by inhibition of ER stress-related apoptosis.ObjectiveIn the present study, we examined whether atorvastatin, when used for pharmacological post-conditioning, improved myocardial ischemia/reperfusion (I/R) injury by inhibition of endoplasmic reticulum (ER) stress-related apoptosis.Methods1. The model of myocardial I/R injury in vivo was made by occluding the left anterior descending artery for 45 min followed by 24 h of reperfusion in SD rats. Animals were divided into 5 groups (n=12 per group):(1) sham group:following thoracotomy, a suture was placed, but the left anterior descending coronary artery was not ligated; (2) I/R group:the left anterior descending coronary artery was ligated for 45 min to induce ischemia, followed by reperfusion for 24 h; (3) ischemia post-conditioning group (I-postC):after ischemia for 45 min,3 cycles of 10-s reperfusion and 10-s ischemia were performed, followed by a final reperfusion for 24 h; (4) low dose atorvastatin post-conditioning group (PPC 0.5mg):after ischemia for 45 min, atorvastatin (in 10% DMSO) was intraperitoneally injected at a dose of 0.5 mg/kg 5 min before reperfusion for 24 h; (5) high dose atorvastatin post-conditioning group (PPC 2mg):after ischemia for 45 min, atorvastatin (in 10% DMSO) was intraperitoneally injected at a 2mg/kg dose 5 min before reperfusion for 24 h;2. A PeriCam PSI bloodstream video monitoring system was used to monitor epicardial perfusion with a monitor;3. Measurement of plasma troponin I (TNI) and lactate dehydrogenase (LDH);4. Measurement of hemodynamics. Indicators include heart rate (HR), ± dp/dtmax, mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP);5. Measurement of infarct area by 2,3,5-triphenyhetrazolium chloride (TTC);6. Detection of myocyte apoptosis by TUNEL staining;7. Western blot assay of ER stress-related apoptosis. Indicators include calreticulin (CRT), glucose-regulated proteins (GRP78), growth arrest and DNA damage inducible gene 153 (CHOP), caspase-12, Bax and Bcl-2;8. Statistical analysis.Results1. Results of atorvastatin post-conditioning affecting myocardial ischemia reperfusion injury.(1) There were no significant differences on blood perfusion between the groups (P>0.05), but there is an increasing trend in group I-postC, PPC0.5mg and PPC2mg comparing with group I/R;(2) I/R significantly increased plasma levels of TNI and LDH (P<0.05 compared to sham). All three post-conditioning treatments significantly decreased plasma levels of TNI and LDH{P<0.05 compared to I/R);(3) The ±dp/dtmax in the I/R group was significantly lower than in the sham group (P<0.05), All postconditioning groups increased the low value seen in the I/R group (P<0.05); The LVEDP of the I/R group was significantly higher than that of the sham group (P<0.05), Although LVEDP was lower in the I-PostC, PPC 0.5 mg, and PPC 2 mg compared with the I/R group, this difference did not reach statistical significance(P>0.05); The MAP in the I/R group was significantly lower than in the sham group (P<0.05). high dose atorvastatin group had significantly higher MAP than the I/R group (P<0.05); There was no significant difference among the five groups in HR(P>0.05);(4) Infarct area of the I-PostC, PPC0.5mg and PPC2mg groups were all significantly lower than that of the I/R group (P<0.05);(5) I/R significantly increased the apoptosis rate (P<0.05 vs. sham), and all postconditioning treatments significantly lowered this rate (all P<0.05 vs. I/R).2. Results of ER stress-related apoptosis.(1) GRP78, CRT, CHOP, Caspasel2, BCL-2, BAX protein expression in the I/R group were significantly higher than that of the sham group (P<0.05);(2) GRP78, CRT, CHOP, Caspasel2 protein expression in all postconditioning treatments were significantly lower than that of the I/R group (P<0.05);(3) BCL-2 protein expression in the PPC2mg were significantly higher than that of the I/R group (P<0.05); BAX protein expression in the I-PostC, and PPC2mg were significantly lower than that of the I/R group (P<0.05).Conclusion:1. Atorvastatin postconditioning have cardioprotective effects by improving myocardial ischemia reperfusion injury similar with I-PostC.2. Atorvastatin post-conditioning improved myocardial ischemia-reperfusion injury possibly by suppressing endoplasmic reticulum (ER) stress-related apoptosis. |
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