GSE135198
Pathways Underlying Impaired Cardiac Preconditioning Potential   in Subjects with the Metabolic Syndrome, and its Restoration by ACE-inhibition
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. Overall design: Experimental animal models: DKO; LDLR-/- and ob/ob)18. C57BL/6 (WT); RNA Extraction and Sequencing; RNA-Seq Data Analysis; Pathway and Regulatory Network Analysis; Ethical committee approval.