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1 Department of Physiology, Faculty of Medicine, University of Porto, Portugal
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Abstract |
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and interleukin 6 overexpression positively correlated with BNP. Inducible NO synthase upregulation was present in both ventricles at 120 min (LV, +327 ± 195%; RV, +311 ± 122%), but only in the RV at 30 min (+256 ± 88%). Insulin-like growth factor 1 increased in both ventricles at 30 (RV, +59 ± 18%; LV, +567 ± 192%) and 120 min (RV, +69 ± 33%; LV, +120 ± 24%). Prepro-endothelin-1 was upregulated in the RV at 120 min (+77 ± 25%). Ca2+-handling proteins were selectively changed in the LV at 120 min (sarcoplasmic reticulum Ca2+ ATPase, 53 ± 7%; phospholamban, +31 ± 4%; Na+–Ca2+ exchanger, 31 ± 6%), while Na+–H+ exchanger was altered only in the RV (–79 ± 5%, 30 min; +155 ± 70%, 120 min). Tumour necrosis factor- and angiotensin converting enzyme were not significantly altered. A very rapid modulation of remote myocardium gene expression takes place during myocardial ischaemia, involving not only the LV but also the RV. These changes are different in the two ventricles and in the same direction as those observed in heart failure.
(Received 20 December 2005;
accepted after revision 9 January 2006; first published online 11 January 2006)
Corresponding author A. F. Leite-Moreira: Department of Physiology, Faculty of Medicine, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal. Email: amoreira{at}med.up.pt
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Introduction |
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Remodelling of the non-infarcted myocardium has been linked to LV dilatation and dysfunction, and the pharmacological inhibition of its molecular pathways was shown to prevent progression towards heart failure, in both experimental models and clinical trials (Shao et al. 1999). Study of gene expression in the non-ischaemic myocardium revealed profound alterations, with induction of molecular fetal phenotype, disturbed expression of Ca2+-handling proteins and local activation of growth-promoting signals (Ono et al. 1998; Shimizu et al. 1998; Shao et al. 1999; Loennechen et al. 2001). In a rat model of left coronary artery (LCA) ligation, the remote myocardium presented atrial natriuretic peptide (ANP), -skeletal actin and ß-myosin heavy chain isoform upregulation, with disturbed gene expression of Ca2+-handling proteins (Shimizu et al. 1998). In a similar model, Loennechen et al. (2001) showed overexpression of endothelin-1 (ET-1) and insulin-like growth factor 1 (IGF-1) in cardiomyocytes isolated from the non-ischaemic myocardium 7 and 42 days after AMI. Cytokine gene expression is also activated both in infarcted and non-ischaemic myocardium. For instance, Ono et al. (1998) showed sustained tumour necrosis factor- (TNF-), interleukin 6 (IL-6) and interleukin 1ß (IL-1ß) upregulation in the remote myocardium 20 weeks after AMI.
In addition, there is increasing evidence that after an LV AMI gene expression is also altered in the right ventricle (RV) and that the changes are different in the two ventricles. In this setting, a microarray profiling study recently showed that rats with LCA ligation had a differential RV and LV expression of more than one thousand genes (Chugh et al. 2003).
Despite extensive evidence for altered gene expression in ischaemic and remote myocardium, leading to biventricular remodelling after AMI, it remains largely unknown how early these changes start in the remote myocardium, which genes are involved, and whether such changes also involve and are similar or not in the contralateral non-ischaemic ventricle. In that context, we examined biventricular function and remote myocardium gene expression of type B natriuretic peptide (BNP), hypoxia-inducible factor 1 (HIF-1(, pro-inflammatory cytokines (TNF- and IL-6), inducible NO synthase (iNOS), growth factors (prepro-endothelin-1 [ppET-1] and IGF-1), angiotensin converting enzyme (ACE), Ca2+-handling proteins (sarcoplasmic reticulum Ca2+ ATPase 2a isoform [SERCA2a], phospholamban [PLB] and Na+–Ca2+ exchanger [NCX]) and Na+–H+ exchanger (NHE), 30 and 120 min after left coronary artery ligation in rats.
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Methods |
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Twenty-seven rats were used for haemodynamic and myocardial gene expression studies, having been randomly assigned to one of two protocols: (i) left coronary artery (LCA) ligation, 1–2 mm distal to the left atrial appendage, for 30 (n= 7) or 120 min (n= 7); or (ii) sham groups of 30 (n= 7) and 120 min (n= 6). Ventricular fibrillation occurred in three rats a few minutes after LCA ligation, and these animals were excluded. Afterwards, no mortality was observed in the studied animals. The ischaemic area induced by LCA ligation was estimated in five additional rats.
Hemodynamic studies
Briefly, anaesthesia was induced and maintained with ketamine hydrochloride (150 mg kg–1, I.P.). Animals were kept at 36–38°C on a heated plate, tracheostomized and mechanically ventilated (Harvard Small Animal Ventilator, model 683). Respiratory frequency and tidal volume were adjusted for the weight of the animal (60 breaths min–1, 1 ml kg–1). The right jugular vein was catheterized (Abocath® 24G) under a dissecting microscope (Leica, Wilde M651), and a continuous infusion of saline (0.9% NaCl; 2 ml h–1) was administered to compensate for perioperative fluid loss. An ECG lead II was recorded throughout.
The heart was exposed through a median sternotomy, and the pericardium was widely opened. RV and LV pressures were measured with a 3 French high-fidelity micromanometer (SPR-524, Millar Instruments, Texas, USA) inserted through the RV free wall into the RV cavity and through an apical puncture incision into the LV cavity. Transducers were calibrated immediately before use, after 30 min of stabilization in a saline bath at 37°C. After complete instrumentation, the animal preparation was allowed to stabilize for 15 min before the beginning of the experimental protocols. Haemodynamic recordings were made with respiration suspended at end-expiration, and they included basal and isovolumetric heartbeats. The latter were obtained by transient (2–3 s) occlusions of the ascending aorta or pulmonary trunk. Parameters were converted on-line to digital data with a sampling frequency of 1 kHz. RV and LV pressures were measured at end-diastole (RVEDP and LVEDP, respectively) and peak systole in basal (RVPmax and LVPmax, respectively) and isovolumetric beats (LVPiso and RVPiso, respectively). Peak rates of RV and LV pressure rise (dP/dtmax) and pressure fall (dP/dtmin) were measured as well. Relaxation rate was estimated with the time constant 
by fitting the isovolumetric pressure fall to a monoexponential function.
Evaluation of the extent of myocardial ischaemia
The ischaemic area was determined in five rats with Evans Blue (Schmidt et al. 1986). Briefly, after LCA ligation, 2 ml of Evans Blue (2 mg ml–1) was injected through the jugular vein to stain the perfused myocardium. Subsequently, the heart was excised, weighed and cut into thin transverse sections of 1–2 mm. Evans Blue-stained myocardium was then carefully dissected under a microscope (Leica, M654) from the unstained portion, and each portion weighed separately. The infarcted area corresponded to the myocardium not stained by Evans Blue. The stained, non-ischaemic myocardium was divided into adjacent and remote areas, according to the distance from the ischaemic area (< 5 mm or > 5 mm, respectively).
Evans Blue infusion revealed that LCA occlusion produced a LV antero-apical and left-sided intraventricular (IV) septal ischaemia, which averaged 35.5 ± 0.6% of the LV + IV septum weight. None of the five rats used to measure ischaemic area showed unstained myocardium in the RV free wall. Accordingly, we collected samples from the posterobasal LV wall and RV free wall for mRNA quantification.
Messenger RNA quantification by real-time RT-PCR
After completion of the haemodynamic studies, the animals were killed with anaesthetic overdose of ketamine, and transmural RV and LV free-wall samples of non-ischaemic remote areas were snap frozen in liquid nitrogen and stored at –70°C. For each region (remote RV and remote LV) and time point (30 and 120 min), we matched samples from animals submitted to ischaemia with animals submitted to the same experimental procedure without LCA ligation (sham).
Total mRNA was extracted through the guanidium-thiocyanate selective silica-gel membrane-binding method (Qiagen 74124, Valencia, USA) according to the manufacturer's instructions. Concentration and purity were assayed by spectrophotometry (Eppendorf 6131000.012).
Two-step real-time RT-PCR was used to perform relative quantification of mRNA. For each studied mRNA molecule, standard curves were generated from the correlation between the amount of starting total mRNA and PCR threshold cycle (second derivative maximum method) of graded dilutions from a randomly selected tissue sample (r > 0.97). For relative quantification of specific mRNA levels, 50 ng of total mRNA from each sample underwent two-step real-time RT-PCR. A melt curve analysis of each real-time RT-PCR and 2% agarose gels (0.5 µg ml–1 ethidium bromide) were performed to exclude primer-dimer formation and assess the purity of the amplification product. In each experimental group, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA levels did not differ significantly between sham and ischaemia conditions, and so GAPDH was used as internal control gene. Results of mRNA quantification are expressed as arbitrary units (a.u.) set as the average value of the sham group (sham = 1 a.u.).
Reverse transcription (10 min at 22°C, 50 min at 50°C and 10 min at 95°C) was performed in a standard thermocycler (Whatman Biometra 050-901) with a total volume of 20 µl: 40 U per reaction of reverse transcriptase (Invitrogen 18064-014), 20 units per reaction of RNase inhibitor (Promega N2515), 30 ng ml–1 random primers (Invitrogen 48190-011), 0.5 mM nucleotide mix (MBI Fermentas R0192), 1.9 mM MgCl2 and 10 mM dithiothreitol (DTT). Ten per cent of the cDNA yield was used as a template for real-time PCR (LightCycler, Roche) using SYBR green (Qiagen 204143) according to the manufacturer's instructions.
Specific PCR primer pairs for the studied genes were: sarcoplasmic reticulum Ca2+ ATPase 2a isoform (SERCA2a), forward
5'-CGA GTT GAA CCT TCC CAC AA-3' and reverse
5'-GGA GGA GAT GAG GTA GCG GAT GGA-3'; phospholamban (PLB), forward
5'-GGC ATC ATG GAA AAA GTC CA-3' and reverse
5'-GGT GGA GGG CCA GGT TGT AA-3'; Na+–Ca2+ exchanger (NCX), forward
5'-CTG GAG CGC GAG GAA ATG TTA-3' and reverse
5'-GAC GGG GTT CTC CAA TCT CAA-3'; Na+–H+ exchanger (NHE), forward
5'-CTG GGC CGG GGT GGA ACA-3' and reverse
5'-AGG CGG AAG ACA GAG GCA GAC G-3'; angiotensin converting enzyme (ACE), forward
5'-GCA GGC CAC CAG GGT CCA CTA CAC-3' and reverse
5'-GAC CTC GCC ATT CCG CTG ATT CT-3'; prepro-endothelin-1 (ET-1), forward
5'-CCA TGC AGA AAG GCG TAA AAG-3' and reverse
5'-CGG GGC TCT GTA GTC AAT GTG-3'; insulin-like growth factor 1 (IGF-1), forward
5'-CAG ACG GGC ATT GTG GAT-3' and reverse
5'-AGT CTT GGG CAT GTC AGT GTG-3'; inducible NO synthase (iNOS), forward
5'-CCC AGC CCA ACA ACA CAG GAT-3' and reverse
5'-GGG CGG GTC GAT GGA GTC A-3'; interleukin 6 (IL-6), forward
5'-CCG TTT CTA CCT GGA GTT TG-3' and reverse
5'-GAA GTT GGG GTA GGA AGG AC-3'; tumour necrosis factor- (TNF-), forward
5'-TGG GCT ACG GGC TTG TCA CTC-3' and reverse
5'-GGG GGC CAC CAC GCT CCT C-3'; natriuretic peptide type B (BNP), forward
5'-TTT GGG CAG AAG ATA GAC C-3' and reverse
5'-CAG AGC TGG GGA AAG AAG-3'; hypoxia-inducible factor-1 (HIF-1), forward
5'-CTA ACA AGC CGG GGG AGG AC-3' and reverse
5'-TCA TAG GCG GTT TCT TGT AGC-3'; and GAPDH, forward
5'-CCG CCT GCT TCA CCA CCT TCT-3' and reverse
5'-TGG CCT TCC GTG TTC CTA CCC-3'.
Statistical analysis
Data are presented as means ±S.E.M. Statistical significance was determined using Student's unpaired t test or ANOVA and Student–Newman–Keuls comparisons for pairwise multiple groups. Linear regression and Pearson correlation coefficients were employed to correlate variables. Differences were considered statistically significant when P < 0.05.
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Results |
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Haemodynamic data are presented in Table 1. LCA ligation induced a significant decrease of LVPiso and LV dP/dtmax at 30 min, which reverted at 120 min. RVPiso and RV dP/dtmax were not significantly altered. Relaxation, assessed by dP/dtmin and time constant , was significantly slowed in the two ventricles both 30 and 120 min after LCA ligation. Of note, LVEDP was increased at both 30 and 120 min after LCA occlusion.
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Gene expression data are illustrated in Figs 1 and 2.
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gene expression was enhanced in the remote LV and RV, although in the latter BNP mRNA levels were increased only 120 min after LCA occlusion.
Analogously, we observed HIF-1 upregulation in the remote myocardium of both ventricles, which was positively correlated with BNP levels (r= 0.514; P < 0.001).
Interleukin 6 mRNA levels were increased in the remote LV at both 30 and 120 min after LCA occlusion. In the RV, IL-6 upregulation was lower and significant only at 120 min. A positive correlation was present between IL-6 and BNP mRNA levels (r= 0.440; P= 0.002). Differently, iNOS overexpression had a similar magnitude in the remote LV and RV, although in the former it was significant only at 120 min. We did not detect alterations in TNF- mRNA levels.
Insulin-like growth factor 1 expression was significantly increased in both ventricles 30 and 120 min after LCA occlusion. However, this upregulation was higher in the remote LV, with an early peak at 30 min. Expression of ppET-1 was slightly but significantly increased only in the RV, 120 min after LCA occlusion. No significant changes were detected in ACE mRNA levels.
Regarding myocardial gene expression of Ca2+-handling proteins, we found significant differences only in the remote LV, 120 min after LCA occlusion; SERCA2a and NCX were downregulated, while PLB was overexpressed. Differently, changes in NHE expression were limited to the RV, being downregulated at 30 min and overexpressed at 120 min.
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Discussion |
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Ligation of the LCA 1–2 mm distal to the left atrial appendage spares the main septal artery and results in a reproducible and widely used experimental model of myocardial infarct (MI; Salto-Tellez et al. 2004). Rodents have intramyocardial coronary arteries and present well-developed septal arteries as the most constant feature of their coronary arrangement. When the main septal artery arises from the LCA, this occurs close to its origin. The LCA distal to this septal artery mainly supplies the LV free wall, although some of its smaller branches also irrigate the left side of the IV septum (Duran et al. 1992). For most studies, the LCA artery is ligated 1–2 mm below the tip of the left auricle in its normal position, which induces roughly 40–50% ischaemia of the LV. Occlusion is confirmed by the change of colour (becoming pale) of the anterior wall of the LV (Tarnavsi et al. 2004). In our study, LCA ligation consistently spared the RV free wall and produced a LV antero-apical and left-sided IV septal ischaemia, which averaged 35.5 ± 0.6% of the LV + IV septum weight. This resulted in transitory LV contractile dysfunction (decreased LVPmax and LV dP/dtmax at 30 min) and persistent biventricular slowing of relaxation (prolonged ). Various mechanisms have been previously shown to compensate for LV contractile dysfunction during acute ischaemia, including ß-adrenergic- and Frank–Starling-mediated enhancement of remote myocardium function (Lew & Ban-Hayashi, 1985). With regard to relaxation impairment, the underlying mechanisms might include disturbed calcium homeostasis, increased non-uniformity and altered loading conditions (Leite-Moreira & Gillebert, 1996), which may also affect the RV through IV septal motion abnormalities (Lancaster et al. 1989) and/or increased pulmonary pressures. Both mechanisms could have been involved in our study because the left-sided IV septum was ischaemic and LVEDP was elevated.
Acute myocardial infarction is associated with overload of the non-ischaemic myocardium, which has been implicated in the local activation of the natriuretic peptides system (Yue et al. 1998). In our study, BNP mRNA levels were significantly elevated in the remote LV 30 min after LCA ligation, confirming the activation of this system in the early acute phase of MI (Hama et al. 1995). Interestingly, the myocardial expression of BNP positively correlated in the present study with IL-6 and HIF-1 mRNA levels in RV and LV remote myocardium.
Recently, HIF-1 expression has been shown to be induced by factors other than hypoxia. Acute and chronic cardiac overload increased HIF-1 gene expression in the myocardium (Kim et al. 2002). The modulation of HIF-1 by load has been proposed to explain the upregulation of this gene in the early adaptation of the remote myocardium after AMI (Kim et al. 2002). This is in accordance with our results, where HIF-1 was increased in the remote myocardium and correlated with BNP mRNA levels.
The inflammatory response is activated in the acute and chronic phases of MI, in both the infarcted and the non-ischaemic myocardium (Ono et al. 1998). This includes production and release of pro-inflammatory cytokines, which modulate cardiac function and myocardial remodelling. We observed a progressive and marked increase in IL-6 gene expression 30 and 120 min after LCA ligation in both ventricles. One of the effects of pro-inflammatory cytokines is iNOS upregulation, which was also increased in our study. NO produced by iNOS in the setting of an ischaemic insult has been associated with the later phase of ischaemic preconditioning (Bolli, 2001). In addition to IL-6, sustained TNF- expression has been documented after AMI in both ischaemic and remote myocardium as soon as 1 day post-MI (Irwin et al. 1999). Although we did not detect any changes in the expression of TNF- in the remote myocardium 30 and 120 min after LCA ligation, this does not preclude a later upregulation of this cytokine. Furthermore, we did not study the infarcted area, which is most likely to be the first area to overexpress TNF- (Irwin et al. 1999). Pro-inflammatory activation in the remote myocardium could also influence the haemodynamic adaptation to AMI. These cytokines have early (< 30 min) and late (24–72 h) negative inotropic effects. Regarding IL-6, both the early and late effect result from intracellular NO-GMPc pathway activation; while the immediate effect depends on the activation of the constitutive, Ca2+-dependent NO synthase, the late effect seems to rely on the inducible form of the enzyme (Kinugawa et al. 1994).
Insulin-like growth factor 1 has been proposed to play a role in remodelling after MI (Palmen et al. 2001). The regulatory mechanisms of IGF-1 expression in the myocardium are not entirely clear. Loennechen et al. (2001) suggested that stretch alone is not a major stimulus for myocardial IGF-1 expression after myocardial infarction in rats. More recently, however, Palmieri et al. (2002) analysed in a very elegant study the effect of graded mechanical stress on myocardial expression of IGF-1. They found that moderate stretch was accompanied by significant upregulation of IGF-1 levels, which appeared maximal after 10 min and remained near identical up to 60 min. In comparison, under severe stretch, a further and progressive increase in IGF-1 levels was observed up to 20 min, which progressively decreased thereafter. This is consistent with our results, which showed a smaller but stable upregulation of IGF-1 mRNA levels in the less overloaded RV, and a striking upregulation of the same gene in the more overloaded remote LV at 30 min that decreased at 120 min. Although IGF-1 effects on myocardial function are still incompletely understood (von Lewinski et al. 2003), its positive inotropic effect could counter-regulate ventricular dysfunction later on after an AMI.
Although multiple lines of evidence have shown the important role of ET-1 and RAA systems in myocardial remodelling, as well as their increased activity in response to a variety of stimuli, including myocardial stretch and ischaemia (Malhotra et al. 1999), we did not detect mRNA upregulation of ACE, while ET-1 mRNA expression was only modestly increased in the RV myocardium 120 min after LCA ligation. This does not exclude early activation of these systems, but rather suggests that, if present, it does not occur at the transcriptional level.
Previous studies have shown altered gene expression of Ca2+-handling proteins in the remote myocardium of failing hearts post-MI (Hasenfuss, 2002). The impairment of myocardial contractility and relaxation has been associated with lower sarcoplasmic reticulum Ca2+ content and reuptake rate, due to reduced SERCA2a activity. In our study, we observed decreased SERCA2a:PLB ratios and NCX expression in the remote LV myocardium, 120 min after LCA occlusion. This could be relevant, given that decreased SERCA2a and NCX activities lead to decreased sarcoplasmic reticulum Ca2+ content and diastolic Ca2+ accumulation, contributing to impaired contractility and relaxation. Interestingly, Omura et al. (2000) found a late (4 months after LCA occlusion), but not an early, SERCA2a and NCX downregulation in a similar experimental model. This suggests a biphasic modulation of gene expression, similar to the double peak of stretch activation responses that have been described for many signalling pathways in the activation and hypertrophic phases of heart failure progression (Hoshijima & Chien, 2002). Of note, this early modulation of gene expression was restricted to the remote LV, reinforcing the concept of different molecular changes in the remote myocardium of the two ventricles after MI (Chugh et al. 2003).
In the mammalian myocardium, intracellular pH regulation by NHE is of special importance because acidosis depresses the contractility in cardiac myocytes by affecting virtually every step in the excitation–contraction coupling (Orchard & Kentish, 1990). However, NHE has also been implicated in the pathogenesis of tissue injury after AMI. In fact, increased NHE expression and activity in the myocardium has been shown in the remote LV, and its inhibition attenuates hypertrophy of the non-ischaemic myocardium and heart failure progression after LCA occlusion (Chen et al. 2004). In our study, early modulation of myocardial NHE expression was restricted to the RV, with decreased mRNA levels at 30 min, followed by overexpression at 120 min. Interestingly we observed a concomitant upregulation of NHE and ppET-1 in the remote RV. This might be relevant, since it has been proposed that NHE overexpression partly mediates the hypertrophic responses to ET-1 (Fliegel & Karmazyn, 2004).
This study provides novel evidence for a rapid modulation of remote non-ischaemic myocardial gene expression acutely after LV AMI, involving not only the LV but also the non-infarcted RV. Such molecular changes are different in the two ventricles and include pro-inflammatory cytokines, growth factors and Ca2+-handling proteins, with alterations in the same direction as those observed in heart failure, indicating its potential implication in ventricular remodelling. Such changes provide an important rationale to suggest the remote LV and RV myocardium as therapeutic targets in the acute phase of a myocardial infarction. Moreover, in view of our results, such targets are not necessarily identical in the two ventricles.
Limitations of the present study
Although the present study describes changes in mRNA expression in the remote myocardium following short periods of ischaemia, we did not evaluate changes in protein content and/or activity. Therefore, we cannot ascertain whether the shift in gene expression is transitional or if it has long-term functional implications.
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Footnotes |
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P < 0.05 versus 30 min; 
P < 0.05 versus RV.