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Alteration of gene expression during progression of hypertension-induced cardiac dysfunction in rats.

ABSTRACT: Hypertension induced by high-salt diet in Dahl salt-sensitive rats leads to compensatory cardiac hypertrophy by approximately 11 wk, cardiac dysfunction at approximately 17 wk, and death from cardiac dysfunction at approximately 21 wk. It is unclear what molecular hallmarks distinguish the compensatory hypertrophy from the decompensated cardiac dysfunction phase. Here we compared the gene expression in rat cardiac tissue from the compensatory hypertrophic phase (11 wk, n = 6) with the cardiac dysfunction phase (17 wk, n = 6) and with age-matched normotensive controls. Messenger RNA levels of 93 genes, selected based on predicted association with cardiac dysfunction, were measured by quantitative real-time PCR. In the hypertrophic phase, the expression of three genes, atrial natriuretic peptide (ANP; P = 0.0089), brain natriuretic peptide (P = 0.0012), and endothelin-1 precursor (P = 0.028), significantly increased, whereas there was decreased expression of 24 other genes including SOD2 (P = 0.0148), sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (P = 0.0002), and ryanodine receptor 2 (P = 0.0319). In the subsequent heart cardiac dysfunction phase, the expression of an additional 20 genes including inducible nitric oxide synthase (NOS; P = 0.0135), angiotensin I-converting enzyme (P = 0.0082), and IL-1beta (P < 0.0001) increased, whereas the expression of seven genes decreased compared with those of age-matched controls. Furthermore, the expression of 22 genes, including prepro-endothelin-1, ANP, angiotensin I-converting enzyme, beta(1)-adrenergic receptor, SOD2, and endothelial NOS, significantly changed in the cardiac dysfunction phase compared with the compensatory hypertrophic phase. Finally, principal component analysis successfully segregated animals with decompensatory cardiac dysfunction from controls, as well as from animals at the compensated hypertrophy phase, suggesting that we have identified molecular markers for each stage of the disease.

SUBMITTER: Koyanagi T

PROVIDER: S-EPMC2494741 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Alteration of gene expression during progression of hypertension-induced cardiac dysfunction in rats.

Koyanagi Tomoyoshi T Wong Lily Y LY Inagaki Koichi K Petrauskene Olga V OV Mochly-Rosen Daria D

American journal of physiology. Heart and circulatory physiology 20080516 1

Hypertension induced by high-salt diet in Dahl salt-sensitive rats leads to compensatory cardiac hypertrophy by approximately 11 wk, cardiac dysfunction at approximately 17 wk, and death from cardiac dysfunction at approximately 21 wk. It is unclear what molecular hallmarks distinguish the compensatory hypertrophy from the decompensated cardiac dysfunction phase. Here we compared the gene expression in rat cardiac tissue from the compensatory hypertrophic phase (11 wk, n = 6) with the cardiac dy ...[more]

PMID: 18487446

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Project description:Coordinated functional balance of negative and positive transcription complexes maintain and accommodate gene expression in hearts during quiescent and hypertrophic conditions, respectively. Negative elongation factor (Nelf) complex has been implicated in RNA polymerase II (pol II) pausing, a widespread regulatory transcriptional phenomenon observed across the cardiac genome. Here, we examine the role of NelfA aka, Wolf-Hirschhorn syndrome candidate 2 (Whsc2), a critical component of the negative elongation complex in hearts undergoing pressure-overload induced hypertrophy. Alignment of high-resolution genome-wide occupancy data of NelfA, Pol II, TFIIB and H3k9ac from control and hypertrophied hearts reveal that NelfA associates with active gene promoters. High NelfA occupancy is seen at promoters of essential and cardiac-enriched genes, expressed under both quiescent and hypertrophic conditions. Conversely, de novo NelfA recruitment is observed at inducible gene promoters with pressure overload, accompanied by significant increase in expression of these genes with hypertrophy. Interestingly, change in promoter NelfA levels correlates with the transcript output in hypertrophied hearts compared to Sham, suggesting NelfA might be playing a critical role in the regulation of gene transcription during cardiac hypertrophy. In vivo knockdown of NelfA (siNelfA) in hearts subjected to pressure-overload results in early ventricular dilatation and dysfunction, associated with decrease in expression of inducible and cardiac-enriched genes in siNelfA hypertrophied compared to control hypertrophied hearts. In accordance, in vitro knockdown of NelfA in cardiomyocytes showed no change in promoter pol II, however significant decrease in in-gene and downstream pol II occupancy was observed. These data suggest an inhibited pol II progression in transcribing and inducible genes, which reflects as a decrease in transcript abundance of these genes. These results indicate that promoter NelfA occupancy is essential for pol II -dependent transcription. Therefore, we conclude that NelfA is required for active transcription and gene expression during cardiac hypertrophy.

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Project description:AimsTakotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that cannot be attributed to a culprit lesion in coronary arteries. Cardiac overstimulation by catecholamines in the setting of stress is implicated in the pathogenesis of TS. While catecholamine-induced alterations in cardiac contractility have been studied as part of the causal pathway in TS, the importance of catecholamine-mediated tachycardia has not been studied. Our aim was to explore whether the reduction in heart rate, either by pharmacological suppression of the sinoatrial node with ivabradine or by surgical induction of third-degree atrioventricular block, prevents isoprenaline-induced TS-like akinesia in an experimental animal model.Methods and resultsWe used 142 female Sprague-Dawley rats in two separate protocols. The TS-like phenotype was induced by an intraperitoneal bolus dose of isoprenaline (ISO) 50 mg/kg. In the first protocol, we randomized 54 rats to ivabradine 10 min before ISO (IVAB1), ivabradine 10 min after ISO (IVAB2), or saline 10 min before ISO (CONTROL). In the second protocol, we randomized 88 rats to surgically induced complete heart block (CHB) or sham operation (CTRL) 10 min before the administration of ISO. All drugs were administered intraperitoneally. We recorded heart rate and blood pressure invasively in the right carotid artery. Cardiac morphology and function were evaluated by high-resolution echocardiography (VisualSonics 770 VEVO, Toronto, Ontario, Canada) 90 min after ISO injection. IVAB1 and IVAB2 rats had significantly lower heart rate and less pronounced TS-like cardiac dysfunction than CONTROL. CHB rats had a lower (54%) heart rate, and no animal developed left ventricular akinesia. In the first protocol, the CONTROL group had a median degree of akinesia of 10.2 [inter-quartile range (IQR) 0.0-18.6]. The IVAB1 group showed a median of akinesia of 0% (IQR 0.0-0.0, P < 0.001 vs. CONTROL). In the IVAB2 group, 5% had TS-like dysfunction (P = 0.001). Ejection fraction was higher in both the IVAB1 (92%, IQR 89-95) and IVAB2 groups (93%, IQR 87-96) than in the CONTROL group (78%, IQR 63-87, P < 0.05). In the second protocol, the median degree of akinesia in the CTRL group was 21.9% (IQR 8.9-24.6). In the CHB group, no rat developed akinesia (median 0%; IQR 0.0-0.0, P < 0.001 vs. CONTROL). Ejection fraction was higher in the CHB group (90%, IQR 87-92) than in the CTRL group (51%, IQR 87-92, P < 0.05).ConclusionsIsoprenaline-induced TS-like cardiac dysfunction can be prevented by lowering heart rate. Tachycardia may be an important part of the causal pathway in TS.

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Alteration of gene expression during progression of hypertension-induced cardiac dysfunction in rats.

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Alteration of gene expression during progression of hypertension-induced cardiac dysfunction in rats.

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