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Argon Induces Protective Effects in Cardiomyocytes during the Second Window of Preconditioning.

ABSTRACT: Increasing evidence indicates that argon has organoprotective properties. So far, the underlying mechanisms remain poorly understood. Therefore, we investigated the effect of argon preconditioning in cardiomyocytes within the first and second window of preconditioning. Primary isolated cardiomyocytes from neonatal rats were subjected to 50% argon for 1 h, and subsequently exposed to a sublethal dosage of hypoxia (<1% O?) for 5 h either within the first (0-3 h) or second window (24-48 h) of preconditioning. Subsequently, the cell viability and proliferation was measured. The argon-induced effects were assessed by evaluation of mRNA and protein expression after preconditioning. Argon preconditioning did not show any cardioprotective effects in the early window of preconditioning, whereas it leads to a significant increase of cell viability 24 h after preconditioning compared to untreated cells (p = 0.015) independent of proliferation. Argon-preconditioning significantly increased the mRNA expression of heat shock protein (HSP) B1 (HSP27) (p = 0.048), superoxide dismutase 2 (SOD2) (p = 0.001), vascular endothelial growth factor (VEGF) (p < 0.001) and inducible nitric oxide synthase (iNOS) (p = 0.001). No difference was found with respect to activation of pro-survival kinases in the early and late window of preconditioning. The findings provide the first evidence of argon-induced effects on the survival of cardiomyocytes during the second window of preconditioning, which may be mediated through the induction of HSP27, SOD2, VEGF and iNOS.

SUBMITTER: Mayer B

PROVIDER: S-EPMC4964531 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Argon Induces Protective Effects in Cardiomyocytes during the Second Window of Preconditioning.

Mayer Britta B Soppert Josefin J Kraemer Sandra S Schemmel Sabrina S Beckers Christian C Bleilevens Christian C Rossaint Rolf R Coburn Mark M Goetzenich Andreas A Stoppe Christian C

International journal of molecular sciences 20160719 7

Increasing evidence indicates that argon has organoprotective properties. So far, the underlying mechanisms remain poorly understood. Therefore, we investigated the effect of argon preconditioning in cardiomyocytes within the first and second window of preconditioning. Primary isolated cardiomyocytes from neonatal rats were subjected to 50% argon for 1 h, and subsequently exposed to a sublethal dosage of hypoxia (<1% O₂) for 5 h either within the first (0-3 h) or second window (24-48 h) of preco ...[more]

PMID: 27447611

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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:The kidneys are prone to developing ischemia reperfusion injury (IRI) following certain renal surgeries and cardiovascular surgeries requiring cardiac arrest. Sevoflurane and ischemic preconditioning reportedly alleviate IRI, which is mediated via microRNAs. The present study compared anesthetic preconditioning (APC) and ischemic preconditioning (IPC) on microRNAs, which promote cell‑survival pathways in rats in a randomized controlled study. After undergoing right nephrectomy under general anesthesia, male Wistar rats (336±24 g) and were divided into four groups (IRI, APC, IPC and sham; n=7 each). The IRI group underwent 45 min clamping of the left renal vasculature, followed by 4 h of reperfusion. APC involved exposure to one minimum alveolar concentration sevoflurane for 15 min. IPC included three cycles of two‑min clamping and five‑min reperfusion. Blood and renal biopsy samples were assessed postoperatively to measure serum creatinine and to analyze renal microRNA (miR) expression using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) testing and their target pathways with Ingenuity Pathway Analysis™. The present study found that serum creatinine values in APC (0.71±0.08 mg/dl) and IPC (0.73±0.1 mg/dl) groups were lower than in the IRI group (0.96±0.13 mg/dl; P<0.05), indicating amelioration of IRI by APC and IPC. RT‑qPCR followed by pathway analysis indicated that APC and IPC affect 'protein kinase B (Akt)'. APC promoted miR‑17‑3p and suppressed miR‑27a. IPC promoted miR‑19a. All the miRs were predicted to regulate phosphorylated Akt, which promotes cell‑protection. Western blot analysis showed that expression of phosphorylated Akt increased and phosphatase and tensin homologue deleted from chromosome 10 (PTEN) decreased following APC and IPC. The present study concluded that APC and IPC affect different miRs, although they are estimated to similarly promote the PTEN/phosphoinositide 3‑kinase/Akt signaling pathway, resulting in reno‑protection.

Project description:BackgroundRepetitive hypoxic preconditioning (RHP) creates an anti-inflammatory phenotype that protects from stroke-induced injury for months after a 2-week treatment. The mechanisms underlying long-term tolerance are unknown, though one exposure to hypoxia significantly increased peripheral B cell representation. For this study, we sought to determine if RHP specifically recruited B cells into the protected ischemic hemisphere, and whether RHP could phenotypically alter B cells prior to stroke onset.MethodsAdult, male SW/ND4 mice received RHP (nine exposures over 2 weeks; 8 to 11 % O2; 2 to 4 hours) or identical exposures to 21 % O2 as control. Two weeks following RHP, a 60-minute transient middle cerebral artery occlusion was induced. Standard techniques quantified CXCL13 mRNA and protein expression. Two days after stroke, leukocytes were isolated from brain tissue (70:30 discontinuous Percoll gradient) and profiled on a BD-FACS Aria flow cytometer. In a separate cohort without stroke, sorted splenic CD19+ B cells were isolated 2 weeks after RHP and analyzed on an Illumina MouseWG-6 V2 Bead Chip. Final gene pathways were determined using Ingenuity Pathway Analysis. Student's t-test or one-way analysis of variance determined significance (P < 0.05).ResultsCXCL13, a B cell-specific chemokine, was upregulated in post-stroke cortical vessels of both groups. In the ischemic hemisphere, RHP increased B cell representation by attenuating the diapedesis of monocyte, macrophage, neutrophil and T cells, to quantities indistinguishable from the uninjured, contralateral hemisphere. Pre-stroke splenic B cells isolated from RHP-treated mice had >1,900 genes differentially expressed by microarray analysis. Genes related to B-T cell interactions, including antigen presentation, B cell differentiation and antibody production, were profoundly downregulated. Maturation and activation were arrested in a cohort of B cells from pre-stroke RHP-treated mice while regulatory B cells, a subset implicated in neurovascular protection from stroke, were upregulated.ConclusionsCollectively, our data characterize an endogenous neuroprotective phenotype that utilizes adaptive immune mechanisms pre-stroke to protect the brain from injury post-stroke. Future studies to validate the role of B cells in minimizing injury and promoting central nervous system recovery, and to determine whether B cells mediate an adaptive immunity to systemic hypoxia that protects from subsequent stroke, are needed.

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Argon Induces Protective Effects in Cardiomyocytes during the Second Window of Preconditioning.

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Argon Induces Protective Effects in Cardiomyocytes during the Second Window of Preconditioning.

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