Abstract
Molecular mechanisms associated with pathophysiological changes in ventricular remodelling due to myocardial infarction (MI) remain poorly understood. We analyzed changes in gene expression by microarray technology in porcine myocardial tissue at 1, 4, and 6 weeks post-MI.MI was induced by coronary artery ligation in 9 female pigs (30–40 kg). Animals were randomly sacrificed at 1, 4, or 6 weeks post-MI (n = 3 per group) and 3 healthy animals were also included as control group. Total RNA from myocardial samples was hybridized to GeneChip® Porcine Genome Arrays. Functional analysis was obtained with the Ingenuity Pathway Analysis (IPA) online tool. Validation of microarray data was performed by quantitative real-time PCR (qRT-PCR).More than 8,000 different probe sets showed altered expression in the remodelling myocardium at 1, 4, or 6 weeks post-MI. Ninety-seven percent of altered transcripts were detected in the infarct core and 255 probe sets were differentially expressed in the remote myocardium. Functional analysis revealed 28 genes de-regulated in the remote myocardial region in at least one of the three temporal analyzed stages, including genes associated with heart failure (HF), systemic sclerosis and coronary artery disease. In the infarct core tissue, eight major time-dependent gene expression patterns were recognized among 4,221 probe sets commonly altered over time. Altered gene expression of ACVR2B, BID, BMP2, BMPR1A, LMNA, NFKBIA, SMAD1, TGFB3, TNFRSF1A, and TP53 were further validated.The clustering of similar expression patterns for gene products with related function revealed molecular footprints, some of them described for the first time, which elucidate changes in biological processes at different stages after MI.
Highlights
Myocardial infarction (MI), generally due to coronary artery occlusion, results in an inappropriate oxygen supply to the downstream myocardium [1]
This study was approved by the Animal Experimentation Unit Ethical Committee of the Catalan Institute of Cardiovascular Sciences (ICCC) (Permit Number: 4563; Departament de Medi ambient i Habitatge (DMAH), Generalitat de Catalunya) and complies with all guidelines concerning the use of animals in research and teaching as defined by the Guide For the Care and Use of Laboratory Animals (NIH Publication No 80-23, revised 1996)
MI alters gene expression in the whole heart In order to analyze changes in gene expression caused by infarct injury in the whole heart, microarray expression profiles of noninfarcted remote myocardium or infarct core samples at each temporal post-MI stage (1, 4, and 6 weeks) were compared with microarray expression profile of control myocardial samples from healthy animals (Fig. 1)
Summary
Myocardial infarction (MI), generally due to coronary artery occlusion, results in an inappropriate oxygen supply to the downstream myocardium [1]. Several studies have analyzed the molecular pathways of LV remodelling, albeit most of them has been performed in small animal models [5,6,7] or has only provided data of individual genes and proteins [8]. Significant differences exist with regard to cardiac characteristics such as heart rate, oxygen consumption, adrenergic receptor ratios, and response to loss of regulatory proteins, when mice are contrasted to humans [9]. The porcine model of MI is extensively used to better understand functional, structural, and molecular changes associated with clinical ischemic heart disease
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