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Ann Thorac Surg 2000;70:2107-2112
© 2000 The Society of Thoracic Surgeons

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Original article: cardiovascular

Inhibition of RNA transcription modulates magnesium-supplemented potassium cardioplegia protection

^a Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

Accepted for publication May 1, 2000.

Address reprint requests to Dr McCully, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Room 140, Boston, MA 02115
e-mail: james_mccully{at}hms.harvard.edu

	Abstract

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Background. Previously we reported that decreased postischemic functional recovery was associated with increased DNA fragmentation in the aged myocardium. Magnesium-supplemented potassium (K/Mg) cardioplegia ameliorated DNA fragmentation and enhanced postischemic functional recovery. We hypothesized that K/Mg cardioprotection might involve either an RNA- or a protein-dependent mechanism.

Methods. Aged rabbit hearts underwent Langendorff perfusion. Global ischemia hearts (GI) received 30 minutes of global ischemia and 60 minutes of reperfusion; K/Mg hearts received cardioplegia before global ischemia. To investigate the role of RNA and protein synthesis, K/Mg hearts were treated with -amanitin or cycloheximide to inhibit RNA or protein synthesis. We also determined the quantity of DNA fragmentation and RNA/DNA ratio.

Results. Inhibition of RNA but not protein synthesis significantly decreased K/Mg cardioprotection and was associated with significantly decreased postischemic functional recovery (p < 0.05 versus K/Mg), increased DNA fragmentation, and decreased RNA/DNA ratio (p < 0.05 versus K/Mg).

Conclusions. These results indicate that K/Mg cardioprotection in the aged myocardium was modulated by an RNA-dependent mechanism.

	Introduction

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With advancing age there are anatomic, mechanical, ultrastructural, and biochemical alterations that compromise the adaptive response of the heart [1, 2]. These alterations cause the senescent myocardium to be less tolerant of surgically induced ischemia and reperfusion than the mature myocardium and aggravate surgical complications in the elderly. In previous reports we have shown that the induction of warm global ischemia resulted in increased cytosolic calcium ([Ca²⁺]_i) accumulation and DNA fragmentation in the aged heart but not the mature heart and that these alterations are associated with decreased postischemic functional recovery in the aged heart but not the mature heart [3–5]. The use of magnesium-supplemented potassium (K/Mg) cardioplegia modulated those effects by ameliorating [Ca²⁺]_i accumulation and DNA fragmentation, which significantly enhanced postischemic functional recovery in the aged myocardium [3–5].

The mechanism(s) that modulate K/Mg cardioprotection remain to be elucidated; however, the association between increased DNA fragmentation and decreased postischemic functional recovery led us to speculate that the mechanism of K/Mg cardioprotection might involve either an RNA- or a protein-dependent mechanism. To investigate this hypothesis, K/Mg cardioplegia was used in concert with -amanitin, a specific RNA polymerase II inhibitor, or cycloheximide, a protein synthesis inhibitor. The hemodynamic and biochemical effects in the aged rabbit heart were evaluated during ischemia and reperfusion.

	Material and methods

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Animals and chemicals
New Zealand white rabbits (n = 54, > 35 months of age) were obtained from Millbrook Farm (Amherst, MA). All animals were housed individually and provided with food and water ab libitum. All experiments were approved by the Beth Israel Deaconess Medical Center Animal Care and Use Committee and conformed to the National Institutes of Health guidelines regulating the care and use of laboratory animals (NIH publication no. 5377-3, 1996). All chemicals used were of electrophoresis grade or ultrapure quality.

Langendorff perfusion
All rabbits were anesthetized with sodium pentobarbital (Veterinary Laboratories, Inc, Lenexa, KS; 100 mg/kg intravenously), and heparin (200 U/kg intravenously) through a marginal ear vein. The heart was excised and used for Langendorff perfusion at a constant pressure of 75 cm H₂O and a constant temperature of 37°C, as previously described [3–5]. Left ventricular (LV) systolic pressure, LV peak developed pressure, LV end-diastolic pressure, and coronary flow were recorded continuously. Hemodynamic variables were acquired using a PO-NE-MAH digital data acquisition system (Gould, Valley View, OH), with an Acquire Plus processor board and LV pressure analysis software. Hearts were perfused for 30 minutes to establish equilibrium hemodynamics. Equilibrium was ceased when heart rate, coronary flow, left ventricular pressure and diastolic pressure were maintained at the same level for three continuous measurement periods 5 minutes apart. Hearts not meeting this criterion were eliminated from the study.

Experimental protocol
All experimental protocols consisted of 30 minutes of equilibrium followed by 60 minutes of preperfusion, 30 minutes of normothermic global ischemia, and 60 minutes of reperfusion. All hearts were paced continuously on the right atrium at 180 ± 3 beats/minute throughout the experiment, using a Medtronic rapid atrial pacer (5330; Medtronic, Minneapolis, MN). Control hearts (n = 8) were perfused for 180 minutes without global ischemia. Global ischemia hearts (GI, n = 8) were preperfused with Krebs-Ringer solution and then received 30 minutes of global ischemia without intervention. Normothermic global ischemia was achieved by cross-clamping the aortic cannula for 30 minutes, followed by 30 minutes of reperfusion. K/Mg hearts (n = 8) were preperfused with Krebs-Ringer solution for 55 minutes and then received K/Mg cardioplegia (20 mmol/L each KCl and MgSO₄ in Krebs-Ringer solution) for 5 minutes before 30 minutes of global ischemia and reperfusion. To determine the effect of inhibition of RNA synthesis on K/Mg cardioprotection, hearts were preperfused for 55 minutes with Krebs-Ringer solution containing -amanitin (2.5 µg/mL; Sigma Chemical Co, St. Louis, MO), a specific RNA polymerase II inhibitor, and then received K/Mg cardioplegia for 5 minutes before 30 minutes of global ischemia and reperfusion (K/Mg + AMN, n = 8). To determine the effect of inhibition of protein synthesis on K/Mg cardioprotection, hearts were preperfused for 55 minutes with Krebs-Ringer solution containing cycloheximide (CHX; 50 µg/mL; Sigma Chemical Co), a protein synthesis inhibitor, and then received K/Mg cardioplegia for 5 minutes before 30 minutes of global ischemia and reperfusion (K/Mg + CHX, n = 8). After reperfusion the hearts were frozen rapidly in liquid nitrogen to allow for subsequent determinations.

The concentrations of -amanitin and cycloheximide were determined on the basis of preliminary studies (data not shown). -Amanitin was investigated at two concentrations based on previous investigations, 2.5 and 5.0 µg/mL, for two preperfusion times, 30 and 60 minutes [6]. Preliminary studies indicated that 60 minutes of preperfusion with Krebs-Ringer solution containing -amanitin at 2.5 µg/mL and 5.0 µg/mL, equally decreased K/Mg cardioprotection but had no effect on myocardial function, RNA-DNA ratio, or DNA fragmentation in control hearts or in GI hearts; therefore, the lower concentration was used. Investigations to determine appropriate CHX concentrations found that there was no difference between 20, 50, and 100 µg/mL; therefore, 50 µg/mL was used in these studies based on previous investigations [7].

Comparison of dry-wet weight ratios
Left ventricular tissue samples (approximately 0.1 g) from all experimental groups were weighed (wet weight) and dried at 80°C for 24 hours for reweighing (dry weight) and then used for the determination of dry-wet weight ratios, as previously described [3, 5].

Isolation of myocardial nuclei and determination of nuclear DNA and RNA
Nonenzymatic differential centrifugation was used to isolate highly purified myocardial nuclei as described by Liew and associates [8]. Myocardial cell nuclear RNA and DNA content were determined according to a procedure previously described [9, 10].

Determination of nuclear DNA fragmentation
Nuclear DNA fragmentation was determined by agarose gel electrophoresis and scanning laser densitometry according to a method previously described [5]. Briefly, after purification DNA underwent agarose gel electrophoresis on a 1.6% agarose gel, and semiquantitative determination of DNA fragmentation was done by scanning laser densitometry using an LKB Ultrascan XL laser densitometer (Pharmacia LKB, Piscataway, NJ). The integral for each blot was calculated using the LKB GelScan XL software program for 1-dimensional analysis. l-DNA (Lambda DNA-Hind III digest, Pharmacia Biotech, Piscataway, NJ) was used as a molecular size standard. Intact DNA was arbitrarily determined to be resolving at greater than or equal to 23 kb. The percentage of DNA fragmentation was determined based on the amount of DNA found to resolve at less than 23 kb [5].

Statistical analysis
Statistical analysis was done with the Systat software package (SPSS Inc, Chicago, IL). The mean ± standard error of the mean for all data were calculated for all variables. Statistical significance was determined using repeated measures analysis of variance with group as a between-subjects factor and time as a within-subjects factor. Post hoc comparisons between groups for both the average effect and at individual time points were made using a Bonferroni correction to adjust for the multiplicity of tests. A one-way analysis of variance was used for RNA-DNA ratio and DNA fragmentation. Statistical significance was claimed only when the confidence level was greater than 95% (p < 0.05).

	Results

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Equilibrium and preperfusion hemodynamics
No significant differences in heart rate, LV systolic pressure, left ventricular end diastolic pressure, left ventricular peak developed pressure (LVPDP), +dP/dt or coronary flow were observed within or between groups following equilibrium or during preperfusion (30 to 85 minutes perfusion).

Left ventricular end-diastolic pressure
Left ventricular end-diastolic pressure was significantly higher throughout reperfusion in GI hearts (p < 0.05 versus K/Mg and control) and was significantly higher in K/Mg + AMN hearts at 40 to 60 minutes reperfusion (150 to 180 minutes perfusion; p < 0.05 versus K/Mg, K/Mg + CHX, and control; Fig 1A). There was no significant difference in left ventricular end-diastolic pressure between GI and K/Mg + AMN hearts at 40 to 60 minutes reperfusion (150 to 180 minutes perfusion). No significant difference in left ventricular end-diastolic pressure was observed within or between control, K/Mg, and K/Mg + CHX hearts during reperfusion. There was no significant difference in left ventricular end-diastolic pressure between GI + AMN, GI + CHX hearts (n = 4 per group), and GI or between control + AMN, control + CHX (n = 3), and control hearts (results not shown).

View larger version (24K): [in this window] [in a new window]   Fig 1. The effects of global ischemia (GI), magnesium-supplemented potassium cardioplegia (K/Mg), K/Mg in which RNA synthesis was inhibited by -amanitin before K/Mg cardioplegia (K/Mg + AMN), and K/Mg in which protein synthesis was inhibited by cycloheximide (K/Mg + CHX; 30 to 90 minutes of perfusion) before 30 minutes of global ischemia (90 to 120 minutes of perfusion) and 60 minutes of reperfusion (120 to 180 minutes of perfusion). (A) Left ventricular end-diastolic pressure (LVEDP); (B) Left ventricular peak developed pressure (LVPDP); (C) Left ventricular positive maximal increase in pressure over time (+dP/dt max). Results are shown as the mean and standard error of the mean for 8 rabbits per group. *Significant differences during reperfusion at p < 0.05 versus K/Mg hearts. (• = Control; = GI; = K/Mg; = K/Mg + AMN; = K/Mg + CHX.)

RNA-DNA ratios
RNA-DNA ratios in myocardial cell nuclei isolated from LV tissue indicated that there was a significant decrease in RNA-DNA ratio after 30 minutes of global ischemia and 60 minutes of reperfusion in K/Mg + AMN and GI hearts (p < 0.05 versus controls, K/Mg, and K/Mg + CHX; Fig 2). There was no significant difference in RNA-DNA ratio between K/Mg + AMN and GI or GI + AMN or GI + CHX hearts. RNA-DNA ratio was 43.1 ± 3.1 µg/mg in control hearts, 41.4 ± 2.6 µg/mg in K/Mg, 39.2 ± 2.1 µg/mg in K/Mg + CHX, 29.3 ± 1.8 µg/mg in K/Mg + AMN, 28.8 ± 1.9 µg/mg in GI, 26.3 ± 2.6 µg/mg in GI + AMN, and 27.5 ± 2.4 µg/mg in GI + CHX hearts. RNA-DNA ratio was 40.7 ± 3.2 µg/mg in control + AMN and 41.3 ± 2.8 µg/mg in control + CHX hearts (n = 3 per group; p > 0.05 versus control; results not shown). There was no significant difference in RNA-DNA ratio between control, K/Mg, and K/Mg + CHX hearts. There was no significant difference in dry-wet weight ratios within or between groups (results not shown).

View larger version (12K): [in this window] [in a new window]   Fig 2. RNA-DNA ratios in myocardial cell nuclei isolated from left ventricular tissue after 30 minutes of global ischemia and 60 minutes of reperfusion in control, K/Mg, K/Mg + CHX, K/Mg + AMN, GI, GI + AMN, and GI + CHX hearts. Results are shown as the mean and standard error of the mean for 8 rabbits per group. Abbreviations as in Fig 1. *Significant differences during reperfusion at p < 0.05 versus K/Mg hearts.

View larger version (34K): [in this window] [in a new window]   Fig 3. (A) Representative gel showing DNA fragmentation in myocardial cell nuclei isolated from left ventricular tissue after 30 minutes of global ischemia and 60 minutes of reperfusion in control, K/Mg, K/Mg + CHX, K/Mg + AMN, GI, GI + AMN, and GI + CHX hearts. (B) Semiquantitative analysis of DNA fragmentation using scanning laser densitometry. Results are shown as the mean and standard error of the mean. Abbreviations as in Fig 1. *Significant differences during reperfusion at p < 0.05 versus K/Mg hearts.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Our results indicated that inhibition of protein synthesis did not affect the cardioprotection afforded by magnesium-supplemented potassium cardioplegia in the aged myocardium, whereas inhibition of RNA synthesis significantly decreased postischemic functional recovery after 30 minutes of normothermic global ischemia (p < 0.05 versus K/Mg, K/Mg + CHX, and control). We also found that, in purified myocardial cell nuclei, there was a significant decrease in the RNA-DNA ratio in GI and K/Mg hearts in which RNA synthesis was inhibited with -amanitin (K/Mg + AMN).

Previous investigations found that after ischemia and reperfusion there are altered messenger RNA transcript levels. Entwistle and colleagues [13] reported changes in various messenger RNAs after ischemia and reperfusion in rabbit hearts, which included increase in heat shock protein 70, c-fos, skeletal -actin, and ryanodine receptor; decrease in ß-adrenergic receptor, tubulin, and phospholamban; and no change in ß-myosin heavy chain, CaATPase, and cardiac -actin. Our data support the hypothesis that RNA synthesis is at least involved in the mechanism(s) leading to enhanced postischemic functional recovery.

Few data are available to indicate whether the messenger RNA synthesized after ischemia and reperfusion ultimately results in the synthesis of myocardial proteins essential for enhanced myocardial functional recovery [14].Our results suggest that the synthesis of de novo proteins might not be involved in the myocardial protection afforded to the aged myocardium by magnesium-supplemented potassium cardioplegia. The use of cycloheximide to inhibit protein synthesis in K/Mg hearts (K/Mg + CHX) did not affect the cardioprotection afforded by K/Mg cardioplegia. This finding agrees with those of Thornton and colleagues [7], who showed that inhibition of protein synthesis with actinomycin D and cycloheximide had no effect on the myocardial protection from infarct afforded by preconditioning. In their rabbit model, preconditioned groups had a greatly reduced infarct size in either the presence or the absence of the protein synthesis inhibitors, actinomycin D and cycloheximide. From those data the authors concluded that protein synthesis had no relation to the mechanism of cardioprotection.

In previous reports we showed that decreased postischemic functional recovery in the aged rabbit heart was associated with increased DNA fragmentation [5]. The use of K/Mg cardioplegia ameliorated those effects, significantly decreasing DNA fragmentation (p < 0.05 versus GI) and significantly enhancing postischemic functional recovery (p < 0.05 versus GI) [5]. In this study we extended those observations and showed that the protection afforded by K/Mg cardioplegia was modulated by inhibition of RNA synthesis, resulting in significantly decreased postischemic functional recovery (p < 0.05vs K/Mg) and significantly increased DNA fragmentation (p < 0.05vs K/Mg). In this study we investigated DNA fragmentation within the limitations of the isolated perfused heart model, which did not allow us to extend the reperfusion time sufficiently such that apoptosis could also be investigated [15].

The mechanism leading to increased DNA fragmentation remains to be elucidated, but previous investigations have shown that in the myocardium myocyte DNA synthesis ceases early in phenotypic development of the myocardium and that DNA and ß polymerase activity in the cardiac myocyte is also decreased such that only maintenance DNA repair is maintained [16]. The age-related reduction of DNA and ß polymerase activity compromises the efficient repair of myocyte nuclear DNA, leading to increased nuclear DNA fragmentation [17]. We have shown that as the heart ages DNA damage occurs and is associated with increased DNA fragmentation, suggesting that DNA polymerase activity is insufficient to allow for proper repair [5].

Sufficient evidence is currently available to indicate that increased DNA fragmentation leads to cell death. Protection from cellular necrosis is afforded partially by DNA nucleotide excision repair mechanisms, which remove and correct injurious DNA damage [18]. Of primary importance in this mechanism is the recognition of damaged DNA sites. Investigation by others has shown that DNA damage is repaired more efficiently in actively transcribed genes and that this repair is directly involved with the transcriptional apparatus [19]. The mechanism of transcription-dependent DNA excision repair has been proposed to involve the stalling of the RNA polymerase II on the DNA template, thus signaling the location of DNA damage and facilitating DNA repair [18]. Our data, which indicate that there was more DNA fragmentation in K/Mg hearts in which RNA polymerase II was selectively inhibited with -amanitin, support the mechanism of transcription-dependent DNA excision repair. Etiologically, such a system would benefit the aging myocardium, with its reduced DNA polymerase activities, by allowing for the more efficient usage of polymerase activity and the maintenance of cellular viability. The transcription itself rather than the transcription of specific genes might provide an endogenous protective mechanism that allows for efficient repair of the genome and amelioration of DNA damage.

The relative contribution of RNA and protein synthesis in the acquisition of cardioprotection has yet to be fully elucidated. In this study we neither investigated the specificity of RNA transcription nor attempted to identify specific gene transcription. Our data suggested that inhibition of RNA synthesis, but not protein synthesis, modulated the cardioprotection afforded by K/Mg cardioplegia in the aged myocardium. These data do not exclude the role of proteins in providing for cardioprotection, as there is sufficient data to suggest that protein phosphorylation, changes in protein conformation, and protein translocation might have essential functions in conferring cardioprotection [20]. The relative synthesis rates and the related mechanisms required for de novo protein intervention, however, make it unlikely that direct transcription-translation linkage is involved in the early stages of cardioprotection.

	Acknowledgments

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Supported by the National Institutes of Health (HL 29077, HL 59542) and the American Heart Association (AHA 95006300).

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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