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Cardiovascular Research 2005 65(2):345-355; doi:10.1016/j.cardiores.2004.10.018
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Copyright © 2004, European Society of Cardiology

Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia–reperfusion injury

Yochai Birnbaum*, Yumei Ye, Salvatore Rosanio, Shahin Tavackoli, Zhao-Yong Hu, Ernst R. Schwarz and Barry F. Uretsky

The Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, 5,106 John Sealy Annex, 301 University Blvd., Galveston, Texas 77555-0553, United States

* Corresponding author. Tel.: +1 409 772 2794; fax: +1 409 772 4982. Email address: yobirnba{at}utmb.edu

Received 19 May 2004; revised 8 October 2004; accepted 13 October 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: Statins attenuate myocardial ischemic injury by activating nitric oxide synthase (NOS). It is unknown whether cyclooxygenase-2 (COX2), which mediates late ischemic preconditioning, also mediates statins-induced cardioprotection. We investigated the involvement of the prostaglandins and NOS in the cardioprotective effect of atorvastatin (ATV) in the rat.

Methods: Sprague–Dawley rats were randomized to a 3-day oral treatment with ATV 10 mg/kg, valdecoxib, a selective COX2 inhibitor (VAL) 3 mg/kg, ATV+VAL or water alone. Rats underwent 30-min myocardial ischemia followed by 4-h reperfusion.

Results: Infarct size was smaller in the ATV group (31.3 ± 1.9%) than controls (44.5 ± 3.1%; p=0.011) and VAL (44.5 ± 3.1%; p=0.008). VAL attenuated the protective effect of ATV when administered together (40.2 ± 2.5%). ATV pretreatment increased myocardial content of 6-keto-PGF1{alpha} (69.5 ± 1.5 pg/mg) and PGE2 (57.9 ± 0.6 pg/mg) compared with controls (16.2 ± 0.2 and 42.1 ± 2.0 pg/mg, respectively) and ATV+VAL (15.8 ± 0.3 and 39.9 ± 1.9 pg/mg, respectively). ATV increased myocardial content of cytosolic phospholipase A2 (cPLA2) (174.8 ± 0.5%), COX2 (446.2 ± 0.9%), PGI2 synthase (201.8 ± 1.1%) and PGE2 synthase (122 ± 0.7%), whereas ATV+VAL did not (123.0 ± 7.9%, 93.8 ± 8.5%, 103.0 ± 1.6% and 99.0 ± 0%, respectively). ATV did not change the myocardial content of eNOS and nNOS, but increased the concentration of phosphorylated eNOS (231.8 ± 2.4%) and iNOS (154.5 ± 1.2%). This effect was not blocked by coadministration of VAL (231.5 ± 3.0% and 154.5 ± 1.8%, respectively).

Conclusions: Our results suggest that the prostaglandins are essential for mediating the myocardial protective effects of ATV and their production is downstream to eNOS phosphorylation and iNOS.

KEYWORDS Cyclooxygenase; Infarction; Phospholipases; Prostaglandins; Statins


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely prescribed for treating hypercholesterolemia and for reducing cardiovascular mortality and morbidity [1]. The beneficial mechanisms of statins likely extend beyond cholesterol lowering [2]. In normocholesterolemic animals, statins significantly reduce cardiac [3–10] and brain [11–14] infarct size. Most investigators have suggested that such protective effects are mediated by enhancement of nitric oxide production caused by increasing endothelial nitric oxide synthase (eNOS) expression via stabilizing eNOS mRNA [8,11,13–17]. However, the steps downstream from eNOS activation have not been clarified.

Cyclooxygenase-2 (COX2), the rate-limiting enzyme in prostaglandin (PG) biosynthesis, is involved in the late phase of ischemic preconditioning, and its effect has been hypothesized to be downstream of eNOS up-regulation [18–21]. The two main cardioprotective products of COX2 in the heart are prostaglandin E2 (PGE2) [22,23] and prostacyclin (PGI2) [24,25].

There are sparse and conflicting data on the effects of statins on the modulation of COX2 expression [26–30]. The present study was designed to investigate the involvement of PG pathways in the cardioprotective actions of atorvastatin (ATV).

We sought to address the following questions: (1) whether the protective effect of ATV is attenuated with a selective COX2 inhibitor; (2) whether cytosolic phospholipase A2 (cPLA2), COX2, PGI2 synthase and PGE2 synthase are up-regulated by ATV; and (3) whether there are interactions between COX2 and eNOS, inducible NOS (iNOS) and neuronal NOS (nNOS) in conferring myocardial protection by ATV.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animal care
All animals received humane care in compliance with ‘The Guide for the Care and Use of Laboratory Animals’ published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996). All experiments were conducted on male Sprague–Dawley rats (body weight: 320–420 g).

2.2. Drugs and pretreatment
Drugs were administered once daily for 3 days by an oral gavage tube. The study drugs were dissolved in 2 ml of water. Rats were randomized to receive (1) ATV 10 mg/kg/day; (2) a selective COX2 inhibitor, valdecoxib (VAL) 3 mg/kg/day; (3) ATV+VAL; or (4) water alone (control) by oral gavage.

2.3. Infarct size surgical protocol
The rat model of myocardial ischemia–reperfusion injury has been described in detail [9,10]. On the fourth day, rats were anesthetized with intraperitoneal injection of ketamine (60 mg/kg) and xylazine (6 mg/kg), intubated and ventilated (FIO2=30%). The left carotid artery was cannulated for monitoring blood pressure and heart rate. The chest was opened and the left coronary artery was encircled with a suture and ligated for 30 min. Thereafter, isofluorane (1–2.5% titrated to effect) was added to maintain anesthesia. Myocardial ischemia was verified by akinesis and discoloration of the ischemia zone. After 30 min of ischemia, the snare was released and myocardial reperfusion was verified by change in the color of the myocardium. Subcutaneous 0.1 mg/kg buprenorphine was administered, the chest was closed and the rats were recovered from anesthesia. Four hours after reperfusion, the rats were reanesthetized, the left coronary artery was reoccluded, 1.5 ml of Evan's blue dye 3% was injected into the right ventricle and the rats euthanized under deep anesthesia.

2.4. Determination of area at risk and infarct size
Hearts were excised and the left ventricle was sliced transversely into six to seven sections. Slices were incubated for 10 min at 37°C in 1% buffered (pH 7.4) 2,3,5-triphenyl-tetrazolium-chloride (TTC), fixed in a 10% formaldehyde and photographed (SPOT RT Slider, Diagnostic Instruments, Sterling Heights, MI; Objective AF MICRO NIKKOR, Japan) in order to identify the ischemic myocardium at risk (uncolored by the blue dye), the necrotic zone (unstained by TTC) and the nonischemic zones (colored by blue dye). The area of ischemia and necrosis in each slice were determined by planimetry, converted into percentages of whole for each slice, and multiplied by the weight of the slice and the results summed to obtain the weight of the myocardial risk area and the weight of the necrotic zone [9,10].

2.5. Enzyme activity analysis
Determinations of enzyme expression and activity were performed on the left anterior ventricular wall samples from hearts of control, ATV and ATV+VAL groups (six rats in each) after the 3-day pretreatment phase (without exposure to ischemia). The rats were anesthetized and sacrificed, and the hearts rapidly explanted, rinsed in cold PBS (pH 7.4), containing 0.16 mg/ml heparin to remove red blood cells and clots, frozen in liquid nitrogen and stored at –70°C. In an additional experiment, rats were treated as above (four rats in each group) and myocardial samples were taken after exposure to 15 min of ischemia for determination of 6-keto-PGF1{alpha} concentrations.

2.6. 6-Keto-PGF1{alpha}, PGF2a, PGE2 and thromboxane B2 levels, and cPLA2 activity
Myocardial samples were homogenized in cold PBS (pH 7.4) and centrifuged. The supernatants were collected and stored on ice. Measurement of 6-keto-PGF1{alpha} (the stable hydrolysis product of PGI2) at baseline, PGF2{alpha} and PGE2 were performed using enzyme immunoassay kits (EIA) (R&D System, Minneapolis, MN). Thromboxane B2, cPLA2 activity and 6-keto-PGF1{alpha} after 15 min of ischemia were measured using EIA kits (Cayman Chemical, Ann Arbor, MI).

2.7. COX1 and COX2 activity
Myocardial samples were sectioned into four segments (20 mg each). The first segment was placed into a test vial with 500 µl Hanks' HEPES solution, the second was placed into 500 µl Hanks' HEPES solution with 50 µM arachidonic acid (AA); the third was placed into 500 µl Hanks' HEPES solution, AA, and 200 µM of SC-58125, a selective COX2 inhibitor (Cayman Chemical); and the fourth was placed into 500 µl Hanks' HEPES solution, AA, and 100 µM of SC-560, a selective COX1 inhibitor (Cayman Chemical) (modified from Ref. [31]). AA was added to bypass a potential rate-limiting effect of cPLA2, thus testing COX1, COX2 and PGI2 synthase activities, with and without the addition of SC-560 and SC-58125. After 15-min incubation at room temperature with gentle shaking, the supernatant in each vial was aspirated and stored at –70°C. The samples (25 µl each) were analyzed for 6-keto-PGF1{alpha}.(Cayman Chemical).

2.8. PGI2 synthase activity
Myocardial samples were sectioned into three segments (20 mg each). The first segment was placed into a test vial with 500 µl Hanks' HEPES solution, the second was placed into 500 µl Hanks' HEPES solution with 150 µM PGH2 (Cayman Chemical); the third was placed into 500 µl Hanks' HEPES solution, 150 µM PGH2, 100 µM of SC-560, and 200 µM of SC-58125. PGH2 and SC-560 and SC-58125 were added to eliminate the potential effects of the upstream enzymes of the PGI2 production (cPLA2, COX1 and COX2). After 20-min incubation at room temperature with gentle shaking, the supernatant in each vial was aspirated and stored at –70°C. The samples (25 µl each) were analyzed for 6-keto-PGF1{alpha} (Cayman Chemical).

2.9. Western immunoblotting
Tissue samples were homogenized in buffer A [25 mM Tris–HCl (pH 7.4), 0.5 mM EDTA, 0.5 mM EGTA, 1 mM phenylmethylsulfonyl fluoride, 1 mM dithiolthreitol, 25 mM NaF, 1 mM Na3VO4 and 1% protease inhibitor (Sigma)] and centrifuged for 15 min at 4°C. The pellets were then incubated on ice in buffer B (buffer A plus 1% Triton X-100) for 2 h and centrifuged for 12 min at 4°C. The resulting supernatants were collected as membranous fractions [20].

Monoclonal anti-cPLA2 antibodies and polyclonal anti-PGI2 synthase antibodies were purchased from Santa Cruz Biotechnology Inc. (Santa Cruz, CA); polyclonal anti-COX2 antibodies, anti-PGE2 synthase, anti-nNOS, and anti-iNOS from Cayman Chemical; anti eNOS antibodies from BD Bioscience (San Jose, CA); and polyclonal anti phosphorylated-eNOS (P-eNOS) antibodies from Molecular Probes (Eugene, OR). The expression of cPLA2, COX2, PGI2 synthase, PGE2 synthase, eNOS, P-eNOS, iNOS and nNOS were assessed by standard SDS-PAGE Western immunoblotting techniques [20]. Protein loading amount and gel transfer efficiency was determined by Ponceau staining [20]. The protein signals and the corresponding records of Ponceau staining of each sample were quantitated by an image scanning densitometer and the strength of each protein signal was normalized to the corresponding Ponceau stain signal [20].

2.10. Immunocytochemistry
Myocardial samples from four rats in each group were cut into transverse sections (18 µm), fixed in acetone/methanol (1:1) and prepared for immunolabeling. The primal antibodies used were those used for the Western blotting, the second antibody were from Sigma (St. Louis, MO). Micrographs were examined on NIKON E600 microscope.

2.11. Statistical analysis
Data are expressed as mean ± SEM. Comparisons among the four groups in the infarct size protocol 1 were done using analysis of variance (ANOVA) with Bonferroni correction for multiple comparisons. Comparisons among the ELISA and Western immunoblotting assays were performed using the Kruskal–Wallis one-way ANOVA on ranks with Dunn correction for multiple comparisons. Mean blood pressure and heart rate were compared using two-way repeated measures ANOVA. Values of p<0.05 were considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Infarct size and area at risk
Of 51 rats, 14 were excluded: 6 rats died during ischemia, 5 had no evidence of ischemia following ligation of the suture and 3 had no evidence of reperfusion following release of the suture. Heart rate (p=0.421) and mean blood pressure (p=0.086) were comparable among groups (data not shown).

Body, left ventricular and the myocardium at risk weights were comparable among groups (Table 1). Infarct size, expressed as a percentage of the myocardium at risk, was significantly smaller in the ATV than in the control group and the VAL group (Table 1). VAL alone did not increase infarct size compared to controls (p=1.0). Infarct size of the ATV+VAL was not statistically significant different from the controls (p=1.0), and VAL (p=1.0), but tended to be larger than in ATV group (p=0.178).


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  		Table 1 Body weight, area at risk and infarct size

 
3.2. Enzyme assays
At baseline, before ischemia, ATV caused a significant increase in the myocardial content of 6-keto-PGF1{alpha} (Fig. 1a). In the ATV+VAL group, there was no increase in 6-keto-PGF1{alpha}. The myocardial levels of 6-keto-PGF1{alpha} after 15 min of ischemia were also significantly elevated in the ATV group (Fig. 1b). Repeating the assay after adding AA with and without the addition of specific COX1 (sc560) and COX2 (sc58125) inhibitors showed that in the control group, there was basal activity of COX1, but the activity of COX2 was negligible (Fig. 2). ATV increased 6-keto-PGF1{alpha} production by COX1 and especially by COX2 (Fig. 2). In the combined treatment group, there was no augmentation of the activity of either COX1 or COX2. In addition, ATV increased the activity of PGI2 synthase (Fig. 3).


Figure 1
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  		Fig. 1 Myocardial content of 6-keto-PGF1{alpha} at baseline (a) and after 15 min of ischemia (b). Myocardial content of PGE2 (c), PGF2{alpha} (d), and thromboxane B2 (e), and cPLA2 activity (f). In the control group, there is production of PGE2, whereas the tissue concentration of 6-keto-PGF1{alpha} and PGF2{alpha} are low. ATV significantly increased the concentrations of 6-keto-PGF1{alpha} and PGE2, but not of PGF2{alpha}. VAL prevented these augmentations by ATV. The myocardial content of thromboxane B2 is low and was not affected by ATV with or without VAL. *p<0.05 vs. ATV.

 

Figure 2
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  		Fig. 2 (a) Generation of 6-keto-PGF1{alpha} in myocardial tissue at baseline (NC), after the addition of arachidonic acid (AA), and after addition of the specific COX2 (sc58125) and COX1 (sc560) inhibitors in the control, ATV and ATV+VAL groups. (b) Generation of 6-keto-PGF1{alpha} by COX1 (AA minus sc560 values for each group). (c) Generation of 6-keto-PGF1{alpha} by COX2 (AA minus sc58125 values for each group). *p<0.05 vs. ATV.

 

Figure 3
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  		Fig. 3 Generation of 6-keto-PGF1{alpha} in myocardial tissue at baseline (NC), after the addition of PGH2, and after addition of PGH2 together with COX1 (sc560) and COX2 (sc58125) inhibitors.

 
ATV also increased the myocardial content of PGE2 (Fig. 1c), but not of PGF2{alpha} (Fig. 1d) and thromboxane B2 (Fig. 1e). Coadministration of VAL prevented the increase in PGE2. ATV augmented the activity of cPLA2. This augmentation was also prevented when VAL was added to ATV (Fig. 1f).

3.3. Western immunoblotting and immunocytochemistry
Pretreatment with ATV resulted in an increase in the content of cPLA2 (Fig. 4a), COX2 (Fig. 4b), PGI2 synthase (Fig. 4c) and PGE2 synthase (Fig. 4d) in the membranous fraction. In the ATV+VAL group, there was no change in these proteins relative to controls.


Figure 4
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  		Fig. 4 Representative immunoblots and densitometric analyses of cPLA2 (a), COX2 (b), PGI2 synthase (c), and PGE2 synthase in the membranous fraction of the heart tissue in the control, ATV, and ATV+VAL groups. *p<0.05 vs. ATV.

 
Fig. 5 depicts immunohistochemistry images of cPLA2, COX2 and PGI2 synthase in the control, ATV and ATV+VAL group, confirming that ATV-induced enhanced expression of all three proteins in both the myocardium and blood vessels and that VAL prevented this increase.


Figure 5
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  		Fig. 5 Immunohistochemistry images of cPLA2, COX2 and PGI2 synthase in the control, ATV and ATV+VAL groups.

 
ATV did not change the myocardial content of eNOS protein (Fig. 6a); however, ATV resulted in a marked increase in the myocardial content of P-eNOS protein (Fig. 6b). In the group pretreated with ATV+VAL, there was no change in the myocardial content of eNOS protein. VAL did not attenuate the increase in the content of P-eNOS protein. ATV increased the expression of iNOS (Fig. 6c). VAL did not attenuate this effect. The expression of nNOS was low and was not affected by either ATV or ATV+VAL treatment (Fig. 6d).


Figure 6
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  		Fig. 6 Representative immunoblots and densitometric analyses of the protein concentration in the membranous fraction of (a) eNOS; (b) P-eNOS; (c) iNOS, and (d) nNOS. *p<0.05 vs. control.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
We found that the cardioprotective effects of ATV are mediated by increased production of PGs achieved by up-regulation of cPLA2, COX2, PGI2 synthase and to a lesser extent, PGE2 synthase. In addition, we found that ATV increased myocardial content of P-eNOS and iNOS. VAL did not block the increase in P-eNOS and iNOS. To our knowledge, this the first demonstration that PG pathways play an essential role in the cardioprotective effects of statins, although it has been previously reported that indomethacin abolished the endothelium-dependent vasodilatatory effect of simvastatin [32]. This is also the first report showing that oral pretreatment with ATV caused an increase in P-eNOS and iNOS concentrations in the heart. Concomitant treatment with VAL did not blunt the increase in P-eNOS and iNOS tissue levels, suggesting that phosphorylation of eNOS and the increase in iNOS concentrations are probably upstream to the activation of cPLA2, COX2 and PGI2 synthase, as suggested for late ischemic preconditioning [18,33].

4.1. Comparison with previous studies
Previous studies have shown that statins reduce myocardial infarct size [3–10]. Most investigators used much lower doses of statins (i.e., simvastatin 1 mg/kg, [4,5,7] or rosuvastatin 0.5 mg/kg [3]); however, the drugs were administered either intravenously [7], intraperitoneally [3,4] or subcutaneously [5]. In a dose ranging study, we have shown that the protective effect of 3-day pretreatment with oral ATV 2 mg/kg/day was smaller than that of 10 mg/kg/day [9]. Subsequently, it was shown that comparable doses of oral simvastatin (20 mg/kg/day) [10] and cerivastatin (0.3 mg/kg/day) [8] reduced myocardial infarct size. Thus, it seems that higher doses of statins are needed when statins are administered orally. Hence, we used the same regimen that was shown to be protective in our previous studies [9,10].

4.2. COX, PGI2 synthase and PGE2 synthase
ATV increased the myocardial contents of PGE2 and especially that of 6-keto-PGF1{alpha} (Fig. 1). ATV significantly increased 6-keto-PGF1{alpha} production by COX2 (Fig. 2) and PGI2 synthase (Fig. 3). The increased production of 6-keto-PGF1{alpha} by COX1 could be explained by the augmentation of PGI2 synthase expression and activity, because production of 6-keto-PGF1{alpha} is dependent on both the COX and PGI2 synthase. Likewise, the prevention of the increased 6-keto-PGF1{alpha} with the combination of ATV and VAL can be related to prevention of the augmentation of PGI2 synthase by VAL (Fig. 3). VAL is considered to be highly selective for COX 2 [34]. Myocardial COX1 activity in the ATV+VAL group was comparable to that of the control group, suggesting that nonselective inhibition of COX1 by VAL is not the explanation for the reduced COX1 activity compared to the ATV group. Immunoblotting showed that ATV increased the tissue concentration of COX2 and PGI2 synthase and to a lesser extent of PGE2 synthase (Fig. 4). Co-administration of VAL with the ATV prevented the increased expression of these enzymes and abolished the infarct size limiting effects of ATV, suggesting that enhanced production of PGs, and especially PGI2, is involved in the protective effect of ATV.

Late ischemic preconditioning causes an increase in myocardial concentrations of PGE2 and 6-keto-PGF1{alpha}, with only a marginal increase in PGF2{alpha} [20]. Previous studies have shown that both intravenous prostacyclin [24,25] and PGE [22,23,35], given before ischemia, reduce myocardial infarct size. Moreover, administration of COX2 inhibitors prior to infarction abrogated the infarct size limiting effects of late ischemic preconditioning [18–21,36]. In the rabbit, administration of {delta}-opioid agonist (BW-373U86) caused myocardial protection and increased the myocardial contents of COX2 protein [19]. On the other hand, in the rat, 24 h after administration of BW-373U86, there was up-regulation of PGI2 synthase, but not COX2 protein [21]. In contrast to our study, which showed activation at baseline before ischemia, the up-regulation of PGI2 synthase with BW-373U86 occurred only after ischemia and reperfusion, but not before ischemia [21]. We found that ATV increased the myocardial content of both COX2 and PGI2 synthase. There are only sparse data on the effects of statins on COX2 expression. Degraeve et al. [26] reported that both mevastatin and lovastatin increased COX2 content and 6-keto-PGF1{alpha} concentration in human aortic smooth muscle cells. Blume et al. [27] reported that COX2 expression increased in interleukin-1β-stimulated mesangial cells after incubation with cerivastatin. On the other hand, three other studies suggested the opposite. Hernandez-Presa et al. [28] showed that ATV reduced the expression of COX2 mRNA and protein in macrophages and smooth muscle cells of hypercholesterolemic rabbits. Inoue et al. [29] found that fluvastatin and simvastatin reduced the concentrations of COX2 mRNA and protein levels in human umbilical vein endothelial cells. Cipollone et al. [30] showed that simvastatin reduced the expression of COX2 in human carotid artery plaques. The effect of statins on PGI2 synthase levels has not been previously reported.

Co-administration of VAL with ATV prevented not only PGs production, but also the increase in the COX2, PGI2 synthase and PGE2 synthase protein concentrations. In contrast to most studies assessing the effects of inhibitors in preventing induction of protection against ischemia reperfusion injury, in the present study VAL was given together with ATV for 3 days and not just prior to ischemia. Previous study showed that aspirin and sodium salicylate prevent the increase in COX2 mRNA and protein levels in stimulated human umbilical vein endothelial cells and human foreskin fibroblasts [37]. Indomethacin reduced COX2 expression in estrogenized rat uterus [38]. Therefore, it is plausible that the inhibition of COX2 activity by VAL induced feedback inhibition and cancelled the ATV-induced stimulation for the increase in the content of COX2, PGI2 synthase and PGE2 synthase.

4.3. cPLA2
The role of cPLA2 in mediating myocardial protection is less clear. It has been suggested that ischemic preconditioning is mediated by activation of cPLA2 leading to increased cellular levels of arachidonic acid that is further metabolized by lipoxygenase [39,40]. The present data indicate that ATV increased the activity and protein content of cPLA2 in the heart (Figs. 1 and 4GoGo). Coadministration of VAL with ATV prevented the activation of cPLA2. Immunohistochemistry demonstrated that the activation occurred both in blood vessels and the myocardium (Fig. 5).

4.4. eNOS phosphorylation
Most investigators suggested that the myocardial protective effect of statins is mediated by increasing eNOS protein expression as a result of stabilizing eNOS mRNA [8,11,13–17]. However, others have suggested that statins may increase the activity of eNOS without altering its absolute concentration by eNOS phosphorylation by the phosphatidyl inositol 3 kinase and protein kinase Akt (PKAkt) signaling cascade [41]. Statins induce phosphorylation of PKAkt [41] and promote translocation of PKAkt to membrane domains in endothelial cells [42]. PKAkt mediated eNOS phosphorylation, leading to increase NO production in human umbilical vein endothelial cells [41]. However, statins did not activate PKAkt phosphorylation in either human saphenous vein smooth muscle cells, rat aorta smooth muscle cells or neonatal rat cardiomyocytes [41]. The stimulatory effect of simvastatin on PKAkt phosphorylation declined by 3 h after exposure and was further reduced at 21 h [41]. Thus, it unclear whether eNOS phosphorylation explains the protective effects of statins in the heart and especially after long exposure to statins. The present study shows for the first time that oral administration of ATV caused a significant increase in P-eNOS concentrations in the heart and that this increase was present after a 3-day treatment, suggesting that eNOS phosphorylation may explain the increased eNOS activity with statins. In contrast to previous studies [8,11,13–17], we did not observe an increase in total eNOS protein after 3-day ATV treatment.

Concomitant treatment with VAL did not blunt eNOS phosphorylation by ATV, suggesting that eNOS phosphorylation is not dependent on PGs generation. This finding is in contrast to Wu et al. [43], who reported that celecoxib blocked the PKAkt phosphorylation in cholangiocarcinoma cells. Previous studies showed that statins do not reduce infarct size in eNOS knockout mice, indicating that eNOS activation is essential for the protective effects of statins [3,11,12,44]. Therefore, eNOS phosphorylation is probably upstream to the activation of cPLA2, COX2, PGI2 synthase and PGE2 synthase, as described for late ischemic preconditioning [18].

4.5. iNOS and nNOS
iNOS mediates the cardioprotective effects of late ischemic preconditioning [33,45,46]. Simvastatin failed to reduce infarct size in iNOS knockout mice [5]. We found that ATV caused a small increase in the expression of iNOS that was not blunted by coadministration of VAL. Fluvastatin and cerivastatin enhanced nitric oxide production as well as iNOS mRNA and protein expression by lipopolysaccharide in vascular smooth muscle cells [47,48]. Previous studies have suggested that iNOS is upstream to COX2 activation in ischemic preconditioning [33]. Shimura et al. [33] found that administration of iNOS inhibitor 24 h after ischemic preconditioning abrogated the increase in myocardial PGE2 and 6-keto-PGF1{alpha}, whereas administration of COX2 inhibitors at the same time did not affect iNOS activity. In another study, Ribeiro et al. [38] reported that iNOS inhibitor reduced the increase in PGE2 and PGF2{alpha} production and COX2 expression induced by lipopolysaccharide injection in estrogenized rat uterus. Chun et al. [49] suggested that Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-kappaB. Thus, it seems that iNOS expression is upstream to the PG pathway activation.

Recently, Wang et al. [50] suggested that nNOS is also involved in the final stage of the late stage (48–72 h after ischemia) of ischemic preconditioning in the rabbit. In our model, 3-day pretreatment with atorvastatin did not alter the expression of nNOS.

It is unclear whether the interaction between COX2 inhibitors and statins has clinical implications. Several retrospective studies suggested that statins, in doses used in the clinical setting, protect the human heart during percutaneous coronary interventions [51,52], coronary artery bypass grafting [53], and major noncardiac vascular surgery [54]. There is a controversy whether selective COX2 inhibitors increase the risk of cardiovascular events [55,56]. It is plausible that COX2 inhibitors might blunt the protective effects of statins and other potential cardioprotective agents.

In conclusion, we found that coadministration of selective COX2 inhibitors attenuated the infarct-size limiting effect of ATV. ATV increased the tissue concentration of cPLA2, COX2, PGI2 synthase and PGE2 synthase. Coadministration of VAL prevented these changes. ATV also increased the tissue concentration of iNOS and P-eNOS without changing the absolute eNOS concentration. This increase was not abrogated by VAL, suggesting that both iNOS expression and eNOS phosphorylation are upstream to the activation of the PG pathway.


   Notes
 
Time for primary review 23 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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