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Molecular Mechanisms Mediating Preconditioning Following Chronic Ischemia Differ from those in Classical Second Window

ABSTRACT: Ischemic preconditioning represents the most powerful mechanism of cardioprotection. The mechanisms mediating the second window of preconditioning (SWOP) differ from those mediating first window preconditioning. We hypothesized that chronic ischemia induced by repetitive ischemic stimuli would be mediated by yet different molecular mechanisms. Accordingly, conscious, chronically instrumented pigs (n=5/group) were submitted to a protocol of classical SWOP (two 10-min episodes of coronary artery occlusion followed by 24 hr reperfusion) and compared to pigs submitted to repetitive occlusion/reperfusion (RCO) by repeating 6 episodes of SWOP 12 hrs apart, and to a model of repetitive coronary stenosis (RCS), in which 6 episodes of 90 min coronary stenosis were performed 12 hrs apart. Microarray analysis was performed on the three models. There was an 85% homology in gene response between both models of RCO and RCS, whereas SWOP was qualitatively different. Both models of RCO and RCS but not SWOP showed a down-regulation of genes encoding proteins involved in oxidative metabolism, and an up-regulation of genes involved in protein synthesis and unfolded protein response, autophagy, heat shock response, protein secretion, and a strong activation of the NF-κB signaling pathway. Two thirds of the genes regulated in the three models showed a gradual pattern of up- or down-regulation, in which RCO was quantitatively intermediary between RCS and SWOP. Therefore, the regulated genes in response to chronic, repetitive episodes of ischemia differ radically from classical first or second window preconditioning.

ORGANISM(S): Sus scrofa

PROVIDER: GSE21096 | GEO | 2010/03/29

SECONDARY ACCESSION(S): PRJNA126691

REPOSITORIES: GEO

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Project description:Ischemic preconditioning represents the most powerful mechanism of cardioprotection. The mechanisms mediating the second window of preconditioning (SWOP) differ from those mediating first window preconditioning. We hypothesized that chronic ischemia induced by repetitive ischemic stimuli would be mediated by yet different molecular mechanisms. Accordingly, conscious, chronically instrumented pigs (n=5/group) were submitted to a protocol of classical SWOP (two 10-min episodes of coronary artery occlusion followed by 24 hr reperfusion) and compared to pigs submitted to repetitive occlusion/reperfusion (RCO) by repeating 6 episodes of SWOP 12 hrs apart, and to a model of repetitive coronary stenosis (RCS), in which 6 episodes of 90 min coronary stenosis were performed 12 hrs apart. Microarray analysis was performed on the three models. There was an 85% homology in gene response between both models of RCO and RCS, whereas SWOP was qualitatively different. Both models of RCO and RCS but not SWOP showed a down-regulation of genes encoding proteins involved in oxidative metabolism, and an up-regulation of genes involved in protein synthesis and unfolded protein response, autophagy, heat shock response, protein secretion, and a strong activation of the NF-ÎºB signaling pathway. Two thirds of the genes regulated in the three models showed a gradual pattern of up- or down-regulation, in which RCO was quantitatively intermediary between RCS and SWOP. Therefore, the regulated genes in response to chronic, repetitive episodes of ischemia differ radically from classical first or second window preconditioning. Four groups of pigs were used for the study, i.e., control (n=5), SWOP (n=5), RCO (n=5), and RCS (n=5). SWOP was induced by two episodes of 10 min coronary artery occlusion (CAO), each followed by 10 min coronary artery reperfusion (CAR). RCO was induced by the same stimulus as SWOP (two cycles of 10 min CAO and 10 min CAR), but repeated six times every 12 hrs. RCS was induced by 90 min low-flow ischemia repeated six times every 12 hrs.

Project description:Aims. The goal of the study was to identify the possible transcriptional alterations responsible for the restoration of the second window preconditioning in the metabolic syndrome heart. Methods. LDLR-/-;ob/ob (DKO) and C57Bl6/J (WT) mice were injected with ACE-inhibitor, captopril (10 mg/kg/day) or NaCl 0.9% as controls. Preconditioning (HPC) was induced by five 6-min cycles at 6% oxygen interposed with 6 min at 21% oxygen. Non-preconditioned mice underwent a sham procedure without hypoxia. Transcriptome analysis (RNA-seq) from the whole heart RNA samples, differential gene expression with Cufdiff, pathway and network analysis with Ingenuity Pathway Analysis (IPA), qRT-PCR, and transcription factor motif enrichment analysis with i-cisTarget were performed. In separate groups, the infarct size was determined histologically after a 30-min occlusion of LAD, followed by 60-min reperfusion. Results. Preconditioning could not reduce infarct size in the untreated DKO mice (1+2%, p>.05). Preconditioning reduced infarct size to 28+2% in WT-HPC and to 23+1% in WTACE-I-HPC, both p<.05. In DKOACE-I hearts, preconditioning potential was partially restored with a reduction of infarct size by 16%. Preconditioning induced low number of differentially expressed genes (DEG) in DKO hearts (29 genes, p<.05) when compared WT and WTACE-I hearts (1634 and 2215 genes respectively, p<.05). In DKOACE-I, the number of DEG after preconditioning increased to 59, p<.05. In the three groups that could phenotypically be protected, preconditioning triggered shared pathways associated with the cell cycle quiescence, such as mTORC2 signaling, eIF2 signaling, regulation of eIF4 and p70S6K signaling, and actin cytoskeleton pathway signaling. The model-specific pathways and transcription factors differed between the groups. In the WT hearts, preconditioning enriched the pathways of mitochondrial biogenesis, oxidative phosphorylation, and anti-apoptotic signalling. In the WTACE-I hearts, preconditioning enriched the pathways of immune system signaling, metabolism, and cell cycle regulation. In the DKOACE-I hearts, pathways associated with negative inotropic effect and inhibition of myocyte growth were enriched after preconditioning. Conclusion. Our findings explain the molecular mechanism behind preconditioning in the healthy and the metabolic syndrome hearts. The phenotypically cardioprotective effect of HPC was absent in the metabolic syndrome hearts and was partially reinstated after ACE-I therapy. Transcriptional response to preconditioning differs between DKO and WT hearts and is model-specific with some degree of overlap.

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Molecular Mechanisms Mediating Preconditioning Following Chronic Ischemia Differ from those in Classical Second Window

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