Myocardial Gene Expression Profiling Research Articles

Myocardial gene expression profiling of rewarming shock in a rodent model of accidental hypothermia

BackgroundSevere accidental hypothermia represents a cardiovascular emergency associated with high mortality and poor recovery of cardiac function. The biochemical changes occurring within the heart during the development of hypothermia and subsequent resuscitation are not known. MethodsBy mRNA expression profiling, we have characterized gene expression changes occurring within the myocardium in an intact rat model of accidental hypothermia during cooling to a core temperature of 15°C and subsequent rewarming to 37°C. During the rewarming phase, these animals develop a profound low-output cardiac failure. ResultsHypothermia induces expression of known mediators of thermotolerance, including heat-shock protein 70 and several factors involved in protection against apoptotic cell death. Upregulation of genes involved in autophagy and increased abundance of autophagosomal vesicles suggest involvement of autophagic degeneration in the development of myocardial dysfunction occurring during rewarming from hypothermia. Rewarming from hypothermia also induces expression of several pro-inflammatory genes involved in the nuclear factor kappa B (NFκB) signaling cascade. ConclusionsOur data demonstrate that rewarming from hypothermia is associated with the induction of a cellular stress–response, including upregulation of autophagy and activation of pro-inflammatory signaling cascades. These data provide a framework for understanding the molecular changes that occur during induction of and rewarming from severe hypothermia, and identifies potential targets for cardioprotective interventions in resuscitation of victims of hypothermia.

Myocardial Alternative RNA Splicing and Gene Expression Profiling in Early Stage Hypoplastic Left Heart Syndrome

Hypoplastic Left Heart Syndrome (HLHS) is a congenital defect characterized by underdevelopment of the left ventricle and pathological compensation of the right ventricle. If untreated, HLHS is invariably lethal due to the extensive increase in right ventricular workload and eventual failure. Despite the clinical significance, little is known about the molecular pathobiological state of HLHS. Splicing of mRNA transcripts is an important regulatory mechanism of gene expression. Tissue specific alterations of this process have been associated with several cardiac diseases, however, transcriptional signature profiles related to HLHS are unknown. In this study, we performed genome-wide exon array analysis to determine differentially expressed genes and alternatively spliced transcripts in the right ventricle (RV) of six neonates with HLHS, compared to the RV and left ventricle (LV) from non-diseased control subjects. In HLHS, over 180 genes were differentially expressed and 1800 were differentially spliced, leading to changes in a variety of biological processes involving cell metabolism, cytoskeleton, and cell adherence. Additional hierarchical clustering analysis revealed that differential gene expression and mRNA splicing patterns identified in HLHS are unique compared to non-diseased tissue. Our findings suggest that gene expression and mRNA splicing are broadly dysregulated in the RV myocardium of HLHS neonates. In addition, our analysis identified transcriptome profiles representative of molecular biomarkers of HLHS that could be used in the future for diagnostic and prognostic stratification to improve patient outcome.

Effects of Levosimendan on Cardiac Gene Expression Profile and Post-Infarct Cardiac Remodelling in Diabetic Goto-Kakizaki Rats

The calcium sensitizer levosimendan has shown beneficial effects on cardiac remodelling in spontaneously diabetic Goto-Kakizaki (GK) rats 12 weeks after experimental myocardial infarction (MI). However, the short-term effects and the cellular mechanisms remain partially unresolved. The aim was to study the effects of oral levosimendan treatment on the myocardial gene expression profile in diabetic GK rats 4 weeks after MI/sham operation. MI was induced to diabetic GK rats. Twenty-four hours after surgery, rats were randomized into four groups: MI, MI +levosimendan (1 mg/kg/day), sham-operated and sham-operated +levosimendan. Cardiac function and histology were examined 1, 4 and 12 weeks after MI. The effects of levosimendan on cardiac gene expression profile were investigated by microarray analysis. Levosimendan ameliorated post-infarct heart failure and cardiac remodelling. Levosimendan altered the expression of 264 of MI and sham rats, respectively; these changes were associated with alterations in two Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Levosimendan up-regulated 3 genes in the renin-angiotensin system pathway [angiotensin receptor 1 (Agtr1), chymase 1 (Cma1) and thimet oligopeptidase 1 (Thop1)] and down-regulated 3 genes in the glycerolipid metabolism pathway [diacylglycerol kinase gamma (Dgkg), carboxyl ester lipase (Cel) and Diacylglycerol kinase iota]. Levosimendan induced opposite effects on the gene expression of pleckstrin homology (PH) domain containing family f (Plekhf1), carboxymethylenebutenolidase homologue (Cmbl) (up-regulation) and hydroxyprostaglandin dehydrogenase 15 (Hpgd) (down-regulation) as compared with MI. MI versus sham affected 420 genes and was associated with alterations in 12 KEGG pathways. The beneficial effects of levosimendan on cardiac hypertrophy in sham-operated GK rats was associated with altered expression in 522 genes and associated with three KEGG pathways including purine metabolism, cell cycle pathway and pathways in cancer. Levosimendan protects against post-infarct heart failure and cardiac remodelling. Analysis of the cardiac transcriptome revealed several genes that are regulated by levosimendan. These genes may represent novel drug targets for heart failure and diabetic cardiomyopathy.

Myocardial gene expression of microRNA-133a and myosin heavy and light chains, in conjunction with clinical parameters, predict regression of left ventricular hypertrophy after valve replacement in patients with aortic stenosis

BackgroundLeft ventricular (LV) reverse remodelling after valve replacement in aortic stenosis (AS) has been classically linked to the hydraulic performance of the replacement device, but myocardial status at the time...

Proteins caught in the proteome of the unloaded remodeling pump

See companion article on page 497. Proteomic profiling of the human failing heart after left ventricular assist device supportThe Journal of Heart and Lung TransplantationVol. 30Issue 5PreviewLeft ventricular assist device (LVAD) support is commonly used in patients with heart failure as a bridge to heart transplantation. Whereas myocardial gene expression profile changes have been well established after LVAD support, the consequences on the protein level largely remain unclear. Full-Text PDF

Proteomic profiling of the human failing heart after left ventricular assist device support

Left ventricular assist device (LVAD) support is commonly used in patients with heart failure as a bridge to heart transplantation. Whereas myocardial gene expression profile changes have been well established after LVAD support, the consequences on the protein level largely remain unclear. Pre-LVAD and post-LVAD myocardial tissue specimens from dilated cardiomyopathy (DCM) and ischemic heart disease (IHD) patients were analyzed by fluorescent 2-dimensional difference gel electrophoresis, and differentially expressed proteins were identified by mass spectrometry. In the DCM group, 16 proteins were detected that showed statistically significant downregulation from pre-LVAD to post-LVAD tissue. In IHD patients, 50 alterations were found, including upregulated (n = 12) and downregulated (n = 38) proteins. The identified proteins in both groups partially overlapped and included proteins from cytoskeleton and mitochondrial energy metabolism. The latter changes were paralleled by severe abnormalities in mitochondrial morphology, as shown by electron microscopy. Post-LVAD proteomes of both DCM and IHD patients largely mimicked the protein profiles of non-failing hearts. Downregulation of the serine protease inhibitor α-1-antichymotrypsin in both DCM and IHD patients after LVAD support was confirmed by immunosorbent assay. LVAD-induced cardiac remodeling in DCM and IHD patients is associated with downregulation of α-1-antichymotrypsin and specific atrophic changes in protein expression profiles predominantly involved in cytoskeleton integrity and mitochondrial energy metabolism.

Serum cardiac troponin I concentrations transiently increase in rats given rosiglitazone

Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist of the thiazolidinedione class, is a major insulin-sensitizing drug widely used to treat type-2 diabetes. Rosiglitazone causes myocardial hypertrophy in rodents and increases the risk of cardiac events in man. To better characterize its cardiac effects, male Wistar rats were orally administered 0, 10 or 80 mg/kg/day rosiglitazone. Myocardial gene expression profiling, hematology, histopathology and clinical chemistry, including measurement of serum cardiac troponin (cTn) I concentration with the ultrasensitive assay, were evaluated after 6 and 24 h and 7 and 14 days of dosing. Heart weight was increased 10% after 7 days and 16% after 14 days of dosing at 80 mg/kg/day in the absence of microscopic changes. At the transcriptomic level, the number of differentially expressed probes was small: it was most at 24 h in rats given 80 mg/kg rosiglitazone with 356 differentially regulated probes (fold change >1.3 fold, p < 0.05). Also, gene categories typically associated with myocardial damage were not over-represented. Most importantly, serum cTnI concentrations in 5/9 rats after 7 days of dosing at 80 mg/kg/day were above the upper limit of serum cTnI concentration. cTnI concentrations after 14 days of dosing were similar between rats given the vehicle and rosiglitazone at 80 mg/kg. This is the first study to detect increases of serum cTnI concentrations in rats administered rosiglitazone. In light of reported cardiac events in patients chronically dosed with PPARγ agonists, our results support serum cTnI concentrations as an early biomarker of cardiac liability.

Myocardial Transcriptional Profiling Reveals a Distint Molecular Signature in Patients With Postpartum Cardiomyopathy

Background: Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening disorder that develops within the last month of pregnancy or the first five months of delivery in previously healthy women. Despite recent advances in the treatment of heart failure, molecular mechanisms of PPCM remain largely unknown and no specific therapy exists for this condition. Methods: Myocardial gene expression profile of age and sex matched subjects with peripartum (PPCM, n = 4), idiopathic (DCM, n = 3), ischemic cardiomyopathy (ICM, n = 3), and non-failing controls (NF, n = 3) were comparatively analyzed.

Acute changes of biventricular gene expression in volume and right ventricular pressure overload

Objective We investigated the effects of acute volume and RV pressure overload on biventricular function and gene expression of BNP, pro-inflammatory cytokines (IL-6 and TNF-α), iNOS, growth factors (IGF-1, ppET-1), ACE and Ca 2+-handling proteins (SERCA2a, phospholamban and calsequestrin). Methods Male Wistar rats ( n = 45) instrumented with pressure tip micromanometers in right (RV) and left ventricular (LV) cavities were assigned to one of three protocols: i) Acute RV pressure overload induced by pulmonary trunk banding in order to double RV peak systolic pressure, during 120 or 360 min; ii) acute volume overload induced by dextran40 infusion (5 ml/h), during 120 or 360 min; iii) Sham. RV and LV samples were collected for mRNA quantification. Results BNP upregulation was restricted to the overloaded ventricles. TNF-α, IL-6, ppET-1, SERCA2a and phospholamban gene activation was higher in volume than in pressure overload. IGF-1 overexpression was similar in both types of overload, but was limited to the RV. TNF-α and CSQ mRNA levels were increased in the non-overloaded LV after pulmonary trunk banding. No significant changes were detected in ACE or iNOS expression. RV end-diastolic pressures positively correlated with local expression of BNP, TNF-α, IL-6, IGF-1, ppET-1 and SERCA2a, while RV peak systolic pressures correlated only with local expression of IL-6, IGF-1 and ppET-1. Conclusions Acute cardiac overload alters myocardial gene expression profile, distinctly in volume and pressure overload. These changes correlate more closely with diastolic than with systolic load. Nonetheless, gene activation is also present in the non-overloaded LV of selectively RV overloaded hearts.

595 Distinct acute myocardial gene expression profiles after pressure and volume overload

595 Distinct acute myocardial gene expression profiles after pressure and volume overload