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ACE-inhibition induces a cardioprotective transcriptional response in the metabolic syndrome heart.

ABSTRACT: Cardiovascular disease associated with metabolic syndrome has a high prevalence, but the mechanistic basis of metabolic cardiomyopathy remains poorly understood. We characterised the cardiac transcriptome in a murine metabolic syndrome (MetS) model (LDLR-/-; ob/ob, DKO) relative to the healthy, control heart (C57BL/6, WT) and the transcriptional changes induced by ACE-inhibition in those hearts. RNA-Seq, differential gene expression and transcription factor analysis identified 288 genes differentially expressed between DKO and WT hearts implicating 72 pathways. Hallmarks of metabolic cardiomyopathy were increased activity in integrin-linked kinase signalling, Rho signalling, dendritic cell maturation, production of nitric oxide and reactive oxygen species in macrophages, atherosclerosis, LXR-RXR signalling, cardiac hypertrophy, and acute phase response pathways. ACE-inhibition had a limited effect on gene expression in WT (55 genes, 23 pathways), and a prominent effect in DKO hearts (1143 genes, 104 pathways). In DKO hearts, ACE-I appears to counteract some of the MetS-specific pathways, while also activating cardioprotective mechanisms. We conclude that MetS and control murine hearts have unique transcriptional profiles and exhibit a partially specific transcriptional response to ACE-inhibition.

SUBMITTER: Yakubova A

PROVIDER: S-EPMC6212468 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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ACE-inhibition induces a cardioprotective transcriptional response in the metabolic syndrome heart.

Yakubova Aziza A Thorrez Lieven L Svetlichnyy Dmitry D Zwarts Liesbeth L Vulsteke Veerle V Laenen Griet G Oosterlinck Wouter W Moreau Yves Y Dehaspe Luc L Van Houdt Jeroen J Cortés-Calabuig Álvaro Á De Moor Bart B Callaerts Patrick P Herijgers Paul P

Scientific reports 20181101 1

Cardiovascular disease associated with metabolic syndrome has a high prevalence, but the mechanistic basis of metabolic cardiomyopathy remains poorly understood. We characterised the cardiac transcriptome in a murine metabolic syndrome (MetS) model (LDLR-/-; ob/ob, DKO) relative to the healthy, control heart (C57BL/6, WT) and the transcriptional changes induced by ACE-inhibition in those hearts. RNA-Seq, differential gene expression and transcription factor analysis identified 288 genes differen ...[more]

PMID: 30385846

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Project description:We propose that the fetal heart is highly resilient to hypoxic stress. Our objective was to elucidate the human fetal gene expression profile in response to simulated ischemia and reperfusion to identify molecular targets that account for the innate cardioprotection exhibited by the fetal phenotype.Primary cultures of human fetal cardiac myocytes (gestational age, 15-20 weeks) were exposed to simulated ischemia and reperfusion in vitro by using a simulated ischemic buffer under anoxic conditions. Total RNA from treated and baseline cells were isolated, reverse transcribed, and labeled with Cy3 or Cy5 and hybridized to a human cDNA microarray for expression analysis. This analysis revealed a highly significant (false discovery rate, <3%) suppression of interleukin 6 transcript levels during the reperfusion phase confirmed by means of quantitative polymerase chain reaction (0.25 +/- 0.11-fold). Interleukin 6 signaling during ischemia and reperfusion was assessed at the protein expression level by means of Western measurements of interleukin 6 receptor, the signaling subunit of the interleukin 6 receptor complex (gp130), and signal transducer of activated transcription 3. Posttranslational changes in the protein kinase B signaling pathway were determined on the basis of the phosphorylation status of protein kinase B, mitogen-activated protein kinase, and glycogen synthase kinase 3beta. The effect of suppression of a prohypertrophic kinase, integrin-linked kinase, with short-interfering RNA was determined in an ischemia and reperfusion-stressed neonatal rat cardiac myocyte model. Endogenous secretion of interleukin 6 protein in culture supernatants was measured by enzyme-linked immunosorbent assay.Human fetal cardiac myocytes exhibited a significantly lower rate of apoptosis induction during ischemia and reperfusion and after exposure to staurosporine and recombinant interleukin 6 compared with that observed in neonatal rat cardiac myocytes ( P < .05 for all comparisons, analysis of variance). Exposure to exogenously added recombinant interleukin 6 increased the apoptotic rate in both rat and human fetal cardiac myocytes ( P < .05). Short-interfering RNA-mediated suppression of integrin-linked kinase, a prohypertrophy upstream kinase regulating protein kinase B and glycogen synthase kinase 3beta phosphorylation, was cytoprotective against ischemia and reperfusion-induced apoptosis in neonatal rat cardiac myocytes ( P < .05).Human fetal cardiac myocytes exhibit a uniquely adaptive transcriptional response to ischemia and reperfusion that is associated with an apoptosis-resistant phenotype. The stress-inducible fetal cardiac myocyte gene repertoire is a useful platform for identification of targets relevant to the mitigation of cardiac ischemic injury and highlights a novel avenue involving interleukin 6 modulation for preventing the cardiac myocyte injury associated with ischemia and reperfusion.

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.

Project description:1. The potential cardioprotective effect of ACE inhibitors has been attributed to the inhibition of bradykinin degradation. Recent data in rats documented a kallidin-like peptide, which mimics the cardioprotective effect of ischaemic preconditioning. This study investigates in isolated Langendorff rat heart the effect of the ACE inhibitor captopril, the role of bradykinin, kallidin-like peptide, and nitric oxide (NO). 2. The bradykinin level in the effluent of the control group was 14.6 pg ml(-1) and was not affected by captopril in the presence or absence of kinin B2-receptor antagonist, HOE140. 3. The kallidin-like peptide levels were approximately six-fold higher (89.8 pg ml(-1)) and increased significantly by treatment with captopril (144 pg ml(-1)), and simultaneous treatment with captopril and HOE140 (197 pg ml(-1)). 4. Following 30 min ischaemia in the control group, the creatine kinase activity increased from 0.4 to 53.4 U l(-1). In the captopril group and in the captopril+L-NAME group, the creatine kinase activity was significantly lower (18.5 and 22.8 U l(-1)). This beneficial effect of captopril was completely abolished by the kinin B2-receptor antagonist, HOE140, as well as by the kallidin antiserum. 5. Perfusion of the hearts with kallidin before the 30 min ischaemia, but not with bradykinin, yielded an approximately 50% reduction in creatine kinase activity after reperfusion. 6. Pretreatment with L-NAME alone and simultaneously with captopril, and with kallidin, respectively, suggests a kinin-independent action of NO before the 30 min ischaemia on coronary flow and a kinin-dependent action after ischaemia. 7. These data show that captopril increases kallidin-like peptide in the effluent. Kallidin-like peptide via kinin B2 receptor seems to be the physiological mediator of cardioprotective actions of captopril against ischaemic reperfusion injury. HOE140 as well as the kallidin antiserum abolished the cardioprotective effects of captopril.

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ACE-inhibition induces a cardioprotective transcriptional response in the metabolic syndrome heart.

Publications

ACE-inhibition induces a cardioprotective transcriptional response in the metabolic syndrome heart.

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