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1Department of Molecular and Cellular Physiology, 2Cardiology Section, Department of Medicine, and 3Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130; Departments of 4Cell Biology and Genetics and 5Vascular Surgery, Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands; and 6Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
Submitted 11 February 2003 ; accepted in final form 22 August 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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-nitro-L-arginine methyl ester (300 mg/kg) pretreatment. Thus genetic overexpression of eNOS in mice attenuates myocardial infarction after MI/R but fails to significantly protect against postischemic myocardial contractile dysfunction in mice.
myocardial infarction; cardiac dysfunction; murine model
A number of previous studies (3, 20, 28–30) have demonstrated that treatment with various NO-donating compounds is highly effective in the setting of myocardial I/R (MI/R) injury. NO has also recently emerged as a crucial modulator of myocardial preconditioning, and both eNOS-derived and inducible NOS (iNOS)-derived NO are thought to mediate cardioprotection during the preconditioning process (33, 36). Furthermore, MI/R injury is significantly enhanced in eNOS-deficient animals compared with wild-type controls (12). Pharmacological inhibition of NO synthesis exacerbates MI/R injury (29), whereas administration of the NO precursor L-arginine can ameliorate MI/R injury (23, 28, 32).
Recently, transgenic (TG) mice that overexpress the eNOS gene have been developed (25, 31). Previous studies of eNOS overexpression have focused primarily on shock states (35) and atherosclerosis (27, 31). While genetic overexpression of eNOS has been shown to protect against endotoxin shock (35), the effects of eNOS overexpression in the setting of hypercholesterolemia and atherogenesis are somewhat controversial at present with conflicting reports in the literature (27, 31).
In the present study, we endeavored to determine whether overexpression of eNOS could affect the severity of MI/R injury in an in vivo murine model of acute myocardial ischemia and reperfusion injury. Specifically, we sought to examine two distinct strains of eNOS TG mice and to evaluate the effects of eNOS overexpression on myocardial infarct size and postischemic myocardial contractile function.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Two distinct strains of eNOS TG mice were utilized in the present study. One eNOS TG mouse was developed in Kobe, Japan (eNOS TG-Kobe), and featured the murine prepoendothelin-1 promoter (GenBank accession no. U07982 [GenBank] ) and bovine eNOS cDNA (GenBank accession no. M99057 [GenBank] ). This mouse was developed on a C57BL/6 background and has been extensively characterized previously (15, 25–27, 34, 35).
An additional eNOS TG mouse was recently developed in Rotterdam (31), The Netherlands (eNOS TG-RT), and these mice were also used in the present study of MI/R injury. A DNA fragment containing the human eNOS gene was isolated from a homemade human genomic cosmid library (10) using eNOS cDNA (kindly donated by Dr. S. Janssens, Leuven, Belgium) as a probe (31). In addition, the DNA fragment contained 
6 kb of the 5' natural flanking sequence, including the native eNOS promoter, and 3 kb of the 3' sequence to the gene. Thus promoter DNA elements were included that have been shown to be essential in transcriptional regulation as well as elements responsible for the tissue distribution of eNOS expression (19). Also, the endothelium enhancer element that is located 4.9 kb upstream from the transcription start site of the eNOS gene is included in this construct. Vector sequences were removed by restriction endonucleases. A solution of 1–2 µg/ml DNA was used for microinjection of fertilized oocytes from FVB donor mice and transplanted into the oviducts of pseudopregnant B10xCBA mice. Founder mice and offspring were genotyped by PCR on DNA isolated from tail biopsies. The primers used were as follows: 5'-GTCCTGCAGACCGTGCAGC-3' (sense) and 5'-GGCTGTTGGTGTCTGAGCCG-3' (anti-sense). Mice were backcrossed to C57BL/6 mice for at least seven generations (99% C57BL/6). The individual performing all experiments was blinded to the mouse genotype until all data were fully analyzed. All experiments performed at Louisiana State University Health Sciences Center conformed to state and federal regulations regarding animal experimentation and with American Physiological Society guidelines.
Myocardial Infarction Protocol
Ligation of the left main coronary artery was performed similar to methods described previously (12, 14). Briefly, mice were anesthetized with intraperitoneal injections of ketamine (50 mg/kg) and pentobarbital sodium (50 mg/kg). The animals were then attached to a surgical board with their ventral side up. The mice were orally intubated with polyethylene (PE)-90 tubing connected to PE-240 tubing and then connected to a model 683 rodent ventilator (Harvard Apparatus; Natick, MA). The tidal volume was set at 2.2 ml, and the respiratory rate was set at 122 breaths/min. The mice were supplemented with 100% oxygen via the ventilator side port. A median sternotomy was performed using an electric cautery, and the proximal left main coronary artery was visualized and completely ligated with 7-0 silk suture mounted on a tapered needle (BV-1, Ethicon).
In additional experiments, both non-TG (NTG) and eNOS TG mice (eNOS TG-Kobe) were subjected to coronary artery ligation for 30 min and 24 h of reperfusion. All of the mice were treated with 5-hydroxydecanoic acid (5-HD) at a dose of 10 mg/kg 30 min before the left main coronary artery ligation (24). An additional group of eNOS TG-Kobe mice (n = 7) were treated with 300 mg/kg N-nitro-L-arginine methyl ester (L-NAME; intraperitoneal injection) 30 min before the left main coronary artery ligation. The mice receiving L-NAME were subjected to 30 min of left main coronary artery ligation and 24 h of reperfusion. Additional experiments were also performed in C57BL/6 mice (n = 6 mice/group) treated with the NO donor dipropylenetriamine (DPTA) NONOate (Alexis Pharmaceuticals; San Diego, CA). In these experiments, mice were subjected to 30 min of myocardial ischemia and 24 h of reperfusion. DPTA NONOate (100 µg/kg) was administered 5 min before coronary artery reperfusion via direct injection into the left ventricular (LV) cavity.
Myocardial Infarct Size Determination
At 24 h of reperfusion, the mice were anesthetized as described previously, intubated, and connected to a rodent ventilator. A catheter (PE-10 tubing) was placed in the common carotid artery to allow for Evans blue dye injection. A median sternotomy was performed, and the left main coronary artery was religated in the same location as before. Evans blue dye (1.2 ml of a 2% solution) was injected into the carotid artery catheter into the heart to delineate the ischemic zone from the nonischemic zone. The heart was rapidly excised and serially sectioned along the long axis in 1-mm-thick sections, which were then incubated in 1.0% 2,3,5-triphenyltetrazolium chloride for 5 min at 37°C to demarcate the viable and nonviable myocardium within the risk zone. Each of the five 1-mm-thick myocardial slices was weighed, and the areas of infarction, risk, and nonischemic LV were assessed by a blinded observer using computer-assisted planimetry (NIH Image 1.57). All of the procedures for area at risk (AAR) and infarct size determination have been previously described (12, 14).
Evaluation of Arterial and LV Hemodynamics
At 7 days after myocardial ischemia and reperfusion, a 1.4-Fr Millar (SPR-671; Houston, TX) pressure transduction catheter was inserted similar to methods described previously (21). Data for each animal were calculated from at least 10 s of chart recording (arithmetic mean of at least 50 cardiac cycles).
Echocardiographic Assessment of LV Function
Transthoracic echocardiography of the LV using a 15-MHz linear array transducer (15L8) interfaced with a Sequoia C256 (Acuson) was performed in groups of mice after either 24 h or 7 days of reperfusion after 30 min of left main coronary artery ligation. Two-dimensional echocardiography was performed as described previously (13, 14). All data were calculated from 10 cardiac cycles/experiment.
Statistical Analyses
Data were analyzed by two-way ANOVA with post hoc analysis using StatView software (version 5.0, SAS Institute; Cary, NC). The Bonferroni test was used for post hoc analysis. Data are reported as means ± SE with differences accepted as significant when P < 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Hemodynamics. Mean arterial blood pressure (Fig. 1) was measured in the eNOS TG-Kobe mice and NTG control animals. Blood pressure was 84 ± 4 mmHg in the NTG group and 77 ± 7 mmHg in the eNOS TG group [P = not significant (NS)]. Similarly, baseline heart rates (Table 1) were similar in the NTG (340 ± 18 beats/min) and eNOS TG (333 ± 10 beats/min) groups.
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Myocardial infarct size. Myocardial AAR per LV and infarct size per AAR data after 30 min of left main coronary artery occlusion and 24 h of reperfusion are presented for NTG controls (n = 11) and eNOS TG mice (n = 10) in Fig. 2. The AARs per LV were similar (P = NS) in the NTG and eNOS TG-Kobe mice (46 ± 3% and 52 ± 3%, respectively). Myocardial infarct size per AAR was 43 ± 3% in the NTG group and 29 ± 4% in the eNOS TG group (P > 0.05 between the groups). In eNOS TG mice treated with L-NAME (n = 7) before myocardial ischemia, the AAR per LV was 58 ± 4% (P = NS compared with NTG and eNOS TG alone), and the myocardial infarct size per AAR was 37 ± 4% (P = NS compared with the NTG group and P < 0.05 compared with the eNOS TG group). In additional experiments, we investigated the effects of L-NAME treatment of eNOS TG mice at dosages of 50 and 100 mg/kg and failed to observe any changes in myocardial infarct size compared with vehicle (data not shown).
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Baseline and postischemic cardiac function after 30-min myocardial infarction and 24 h of reperfusion. Baseline and postischemic cardiac function data are presented in Tables 1 and 2. No group differences in heart rate, stroke volume, cardiac output, LV end-diastolic diameter, LV end-systolic diameter, or fractional shortening were observed at baseline. After myocardial ischemia and reperfusion, the heart rate was significantly (P < 0.05) reduced in both the NTG and eNOS TG groups compared with baseline values. Furthermore, stroke volume and fractional shortening were also significantly (P < 0.05 vs. baseline) depressed in the NTG and eNOS TG groups after 30 min of myocardial ischemia and 24 h of reperfusion.
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Baseline and postischemic cardiac function after 30-min myocardial infarction and 7 days of reperfusion. An additional group of eNOS TG-Kobe mice was subjected to myocardial ischemia for 30 min followed by 7 days of reperfusion, and cardiac function was assessed. LV fractional shortening data (two-dimensional echocardiography) are presented in Fig. 3. Baseline fractional shortening was 28 ± 2% in NTG mice and 27 ± 1% in eNOS TG mice (P = NS). After MI/R, fractional shortening was 27 ± 3% in the NTG group and 24 ± 3% in the eNOS TG group (P = NS). Additional data for LV pressures (LV Millar catheter) are presented in Figs. 4 and 5 after myocardial infarction and 7 days of reperfusion. LV endsystolic pressure was 90 ± 2 mmHg in the NTG group and 85 ± 9 mmHg in the eNOS TG group (P = NS). LV end-diastolic pressures were 16 ± 6 mmHg in the NTG group and 3 ± 2 in the eNOS TG group (P < 0.05). LV developed pressure was 74 ± 5 mmHg in the NTG mice and 82 ± 9 in the eNOS TG mice (P = NS).
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Data for the first derivative of LV pressure (LV dP/dt) are presented in Fig. 5. Positive dP/dt was similar (P = NS) in the NTG and eNOS TG groups (4,675 ± 1,195 and 6,300 ± 1,980 mmHg/s, respectively). Negative dP/dt was –3,750 ± 992 mmHg/s in the NTG animals and –6,700 ± 2,215 mmHg/s in the eNOS TG-Kobe animals (P = NS).
eNOS TG-RT Mice
Myocardial ischemia-reperfusion. Myocardial ischemia (30 min) and reperfusion (24 h) experiments were also performed in the eNOS TG-RT mouse strain. The results of these experiments are presented in Figs. 6 and 7. Mean arterial blood pressure data are shown in Fig. 6. Baseline blood pressure was 86 ± 5 mmHg in the NTG mice and 80 ± 3 mmHg in the eNOS TG mice (P = NS). The blood pressure during ischemia was reduced to 59 ± 5 mmHg in the NTG group and to 55 ± 3 mmHg in the eNOS TG group (P < 0.05 vs. baseline for both groups; P = NS between groups). After reperfusion, mean arterial blood pressure remained significantly depressed in both groups (P < 0.05 vs. baseline).
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Myocardial infarct data for the eNOS TG-RT mice are presented in Fig. 7. The AAR per LV was 51 ± 4% in the NTG controls and 48 ± 7% in the eNOS TG group (P = NS). Myocardial infarct size per AAR was significantly (P < 0.05) reduced in the eNOS TG group (34 ± 3%) compared with the NTG group (50 ± 7%).
eNOS TG-Kobe Mice with 5-HD Treatment
Myocardial infarct size. The effects of the mitochondrial ATP-sensitive K+ (KATP) channel blocker 5-HD on myocardial infarct size in NTG mice and the eNOS TG-Kobe strain of mice are presented in Fig. 8. Treatment with 5-HD failed to attenuate myocardial infarct size in both the eNOS TG group (P = NS vs. no treatment) and the NTG group (P = NS vs. no treatment).
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Wild-Type Mice with NO Donor Therapy
Myocardial infarct size. The effects of NO donor therapy (DPTA NONOate) were evaluated in NTG wild-type mice (n = 6 mice/group), and these data are presented in Fig. 9. The AAR per LV was 61 ± 4% in untreated wild-type mice and 63 ± 4% in wild-type mice treated with DPTA (P = NS between groups). Infarct size per AAR was 45 ± 3% in wild-type controls and 21 ± 2% in mice treated with DPTA (P < 0.01 between groups).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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33% in two distinct strains of eNOS TG mice. The bovine eNOS gene was overexpressed in one mouse strain, whereas the human eNOS gene was overexpressed in the other mouse strain. eNOS genetic expression varied from 6- to 12-fold in these TG mice, and eNOS protein expression was confined primarily to the vascular endothelium (13, 25, 27, 31). All of these improvements occurred in the eNOS TG mice without changes in systemic hemodynamics or differences in baseline ventricular morphology and function. Despite the significant reduction in myocardial infarct size, we failed to observe any significant preservation of postischemic myocardial contractile function as assessed by echocardiography or by LV direct catheterization experiments when mice were evaluated at 24 h or 7 days after myocardial infarction. It is likely that the reduction in myocardial infarct size, although significant, was not of a great enough magnitude to induce protection against postischemic contractile dysfunction. Treatment of eNOS TG mice with the NOS inhibitor L-NAME attenuated the cardioprotection observed with eNOS overexpression. These data support a cardioprotective role for eNOS in MI/R injury and further support previous studies of eNOS-deficient mice and studies of NO donors in acute MI/R injury. Previous experimental studies of eNOS TG mice have revealed a very interesting phenotype that results from genetic overexpression of eNOS. eNOS TG mice have been shown to be protected against endotoxin shock (35) and to display systemic hypotension (25, 31). The eNOS TG mice display reduced NO-mediated vasodilator responses and appear to exhibit a nitrate tolerance (25, 34). Additionally, eNOS overexpression has been shown to limit neointimal lesion formation and medial thickening in a model of vascular remodeling (15). Overexpression of eNOS has also been shown to protect against skeletal muscle I/R injury (26). Reductions in skeletal muscle I/R injury were accompanied by a reduction in leukocyte-endothelial cell adhesion molecules and leukocyte trafficking into the ischemic tissue (26). Our laboratory has recently demonstrated (13) that genetic overexpression of eNOS significantly attenuates the severity of congestive heart failure after severe myocardial infarction in mice. Our previous study (13) clearly demonstrated significant improvements in survival and cardiac function at 30 days after myocardial infarction in the eNOS TG-RT mouse compared with NTG controls. The role of eNOS-derived NO in atherogenesis has been extensively investigated. Two strains of eNOS TG mice have been bred with apolipoprotein E-deficient mice as a means to study the potential role of NO in atherosclerosis. Interestingly, conflicting reports have emerged, with one group reporting that eNOS overexpression accelerates atherosclerotic lesion formation (27) and the other group reporting attenuated atherosclerotic lesion formation (31). Finally, both eNOS and iNOS have been selectively overexpressed within cardiac myocytes (1, 6). Cardiac myocyte-specific eNOS overexpression has been shown to blunt cardiac myofilament Ca2+ sensitivity without any alterations in systemic hemodynamics (1), whereas cardiac-specific iNOS overexpression did not alter cardiac function (6).
Our laboratory and others (3, 20, 23, 28–30) have previously reported that NO-donating agents significantly reduce the extent of myocardial reperfusion injury in various animal model systems. In addition, our laboratory and others have previously demonstrated that exogenous NO therapy does protect against postischemic myocardial contractile dysfunction (3, 28, 29) and that inhibition of NO promotes postischemic myocardial contractile dysfunction (5, 28). Furthermore, genetic deficiency of the eNOS enzyme significantly exacerbates MI/R injury (12). The present study provides additional support for the cardioprotective actions of NO in the setting of myocardial reperfusion injury. However, the extent of myocardial infarct size reduction observed in the present study (i.e., 32–33%) was significantly less than that reported in previous studies of exogenous NO donors (i.e., >50–65% reductions in infarct size). Furthermore, we administered the NO donor DPTA NONOate to wild-type mice in the present study and observed a highly significant 53% reduction in myocardial infarct size. One possible explanation for this apparent discrepancy is that the eNOS TG mice are exposed to elevated NO levels from the time of birth (i.e., chronic exposure), whereas NO donors have been administered to wild-type animals only for a short period of time. Thus chronic exposure to elevated eNOS and NO levels may induce myocardial tolerance, resulting in a reduction in myocardial protection compared with treatment of naïve mice with NO-donating agents. This observation may have important implications for the use of gene therapy. A previous study (34) has revealed that eNOS TG mice are resistant to NO/cGMP signaling. A recent study (2) has also demonstrated that eNOS overexpression protects isolated perfused hearts against myocardial reperfusion injury. Brunner et al. (2) demonstrated significant cardioprotection in gene-targeted mice with cardiac myocyte-specific overexpression of eNOS. Experiments utilizing a conditional transgenesis approach may provide important new insights regarding eNOS overexpression and MI/R injury.
The primary mechanism(s) responsible for the observed cardioprotective effects in the two strains of eNOS TG mice remains unknown. Future studies in our laboratory will focus on the elucidation of the precise cellular mechanisms responsible for cytoprotection in the eNOS TG mice. NO derived from eNOS has a highly diverse biological profile that includes antiplatelet (21) and antileukocyte actions (16), vasodilator effects (7, 26), and direct cytoprotective actions (11). It is likely that the cardioprotective actions observed in eNOS TG mice are the result of a number of these actions of NO. Recently, experimental evidence indicated that NO can modulate mitochondrial KATP channels in the setting of myocardial preconditioning and thereby induce myocardial protection (23). We treated both NTG and eNOS TG mice with a selective inhibitor of mitochondrial KATP channels before the onset of myocardial ischemia and observed no attenuation of myocardial infarct size. These data suggest that the reduction in myocardial infarct size observed in the eNOS TG mouse is not dependent on activation of mitochondrial KATP channels in the myocardium.
In summary, overexpression of the eNOS enzyme significantly attenuates the extent of myocardial infarct size after coronary artery ischemia and reperfusion. These data provide clear evidence of the beneficial role of enhanced eNOS-derived NO production during myocardial reperfusion injury. Future studies should be directed toward identifying the mechanism of this protective effect. In the future, therapies might be developed to improve vascular eNOS function as a means to improve outcomes in patients suffering from acute myocardial infarction.
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ACKNOWLEDGMENTS |
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This study was funded by National Institutes of Health Grants RO1 HL-60849 and PO1 DK-43785 (to D. J. Lefer).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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