Dataset Information

Remote ischemic preconditioning attenuates intestinal mucosal damage: insight from a rat model of ischemia-reperfusion injury.

ABSTRACT:

Background

Remote ischemic preconditioning (RIPC) is a phenomenon, whereby repeated, non-lethal episodes of ischemia to an organ or limb exert protection against ischemia-reperfusion (I/R) injury in distant organs. Despite intensive research, there is still an apparent lack of knowledge concerning the RIPC-mediated mechanisms, especially in the intestine. Aim of this study was to evaluate possible protective effects RIPC on intestinal I/R injury.

Methods

Thirty rats were randomly assigned to four groups: I/R; I/R?+?RIPC; Sham; Sham?+?RIPC. Animals were anesthetized and the superior mesenteric artery was clamped for 30 min, followed by 60 min of reperfusion. RIPC-treated rats received 3?×?5 min of bilateral hindlimb I/R prior to surgery, sham groups obtained laparotomy without clamping. After I/R injury serum/tissue was analyzed for: Mucosal damage, Caspase-3/7 activity, expression of cell stress proteins, hydrogen peroxide (H₂O₂) and malondialdehyde (MDA) production, Hypoxia-inducible factor-1? (HIF-1?) protein expression and matrix metalloproteinase (MMP) activity.

Results

Intestinal I/R resulted in increased mucosal injury (P?2O₂ and MDA remained unchanged after RIPC, while the reduced intestinal injury was associated with increased HIF-1? levels. Measurements of MMP activities in serum and intestinal tissue revealed an attenuated gelatinase activity at 130 kDa within the serum samples (P?ConclusionsRIPC ameliorates intestinal I/R injury in rats. The underlying mechanisms may involve HIF-1? protein expression and a decreased serum activity of a 130 kDa factor with gelatinase activity.

SUBMITTER: Hummitzsch L

PROVIDER: S-EPMC6489261 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Remote ischemic preconditioning attenuates intestinal mucosal damage: insight from a rat model of ischemia-reperfusion injury.

Hummitzsch Lars L Zitta Karina K Berndt Rouven R Wong Yuk Lung YL Rusch Rene R Hess Katharina K Wedel Thilo T Gruenewald Matthias M Cremer Jochen J Steinfath Markus M Albrecht Martin M

Journal of translational medicine 20190429 1

<h4>Background</h4>Remote ischemic preconditioning (RIPC) is a phenomenon, whereby repeated, non-lethal episodes of ischemia to an organ or limb exert protection against ischemia-reperfusion (I/R) injury in distant organs. Despite intensive research, there is still an apparent lack of knowledge concerning the RIPC-mediated mechanisms, especially in the intestine. Aim of this study was to evaluate possible protective effects RIPC on intestinal I/R injury.<h4>Methods</h4>Thirty rats were randomly ...[more]

PMID: 31036020

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Project description:Ischemic preconditioning (IPC) has a strong renoprotective effect during renal ischemia/reperfusion (I/R) injury that is thought to relate to autophagy. However, the role of autophagy during IPC-afforded renoprotection and the precise mechanisms involved are unknown. In this study, an in vitro hypoxia/reoxygenation (H/R) model was established in which oxygen and glucose deprivation (OGD) was applied to renal cells for 15 h followed by reoxygenation under normal conditions for 30 min, 2 h or 6 h; transient OGD and subsequent reoxygenation were implemented before prolonged H/R injury to achieve hypoxic preconditioning (HPC). 3-Methyladenine (3-MA) was used to inhibit autophagy. In a renal I/R injury model, rats were subjected to 40 min of renal ischemia followed by 6 h, 12 h or 24 h of reperfusion. IPC was produced by four cycles of ischemia (8 min each) followed by 5 min of reperfusion prior to sustained ischemia. We found that IPC increased LC3II and Beclin-1 levels and decreased SQSTM/p62 and cleaved caspase-3 levels in a time-dependent manner during renal I/R injury, as well as increased the number of intracellular double-membrane vesicles in injured renal cells. IPC-induced renal protection was efficiently attenuated by pretreatment with 5 mM 3-MA. Pretreatment with IPC also dynamically affected the expression of SGK1/FOXO3a/HIF-1α signaling components. Moreover, knocking down SGK1 expression significantly downregulated phosphorylated-FOXO3a (p-FOXO3a)/FOXO3 and HIF-1α, suppressed LC3II and Beclin-1 levels, increased SQSTM/p62 and cleaved caspase-3 levels, and abolished the protective effect of IPC against I/R-induced renal damage. SGK1 overexpression efficiently increased p-FOXO3a/FOXO3 and HIF-1α levels, promoted the autophagy flux and enhanced the protective effect mediated by HPC. Furthermore, FOXO3a overexpression decreased HIF-1α protein levels, inhibited HIF-1α transcriptional activity and reduced the protective effect of IPC. Our study indicates that IPC can ameliorate renal I/R injury by promoting autophagy through the SGK1 pathway.

Project description:BackgroundTo study the protective effects of delayed remote ischemic preconditioning (RIPC) against spinal cord ischemia-reperfusion injury (SCIRI) in mice and determine whether SIRT3 is involved in this protection and portrayed its upstream regulatory mechanisms.MethodsIn vivo, WT or SIRT3 global knockout (KO) mice were exposed to right upper and lower limbs RIPC or sham ischemia. After 24 h, the abdominal aorta was clamped for 20 min, then re-perfused for 3 days. The motor function of mice, number of Nissl bodies, apoptotic rate of neurons, and related indexes of oxidative stress in the spinal cord were measured to evaluate for neuroprotective effects. The expression and correlation of SIRT3 and NMDAR were detected by WB and immunofluorescence. In vitro, primary neurons were exacted and OGD/R was performed to simulate SCIRI in vivo. Neuronal damage was assessed by observing neuron morphology, detecting LDH release ratio, and flow cytometry to analyze the apoptosis. MnSOD and CAT enzyme activities, GSH and ROS level were also measured to assess neuronal antioxidant capacity. NMDAR-AMPK-PGC-1α signaling was detected by WB to portray upstream regulatory mechanisms of RIPC regulating SIRT3.ResultsCompared to the SCIRI mice without RIPC, mice with RIPC displayed improved motor function recovery, a reduced neuronal loss, and enhanced antioxidant capacity. To the contrary, the KO mice did not exhibit any effect of RIPC-induced neuroprotection. Similar results were observed in vitro. Further analyses with spinal cord tissues or primary neurons detected enhanced MnSOD and CAT activities, as well as increased GSH level but decreased MDA or ROS production in the RIPC + I/R mice or NMDA + OGD/R neurons. However, these changes were completely inhibited by the absence of SIRT3. Additionally, NMDAR-AMPK-PGC-1α signaling was activated to upregulate SIRT3 levels, which is essential for RIPC-mediated neuroprotection.ConclusionsRIPC enhances spinal cord ischemia tolerance in a SIRT3-dependent manner, and its induced elevated SIRT3 levels are mediated by the NMDAR-AMPK-PGC-1α signaling pathway. Combined therapy targeting SIRT3 is a promising direction for treating SCIRI.

Dataset Information

Remote ischemic preconditioning attenuates intestinal mucosal damage: insight from a rat model of ischemia-reperfusion injury.

Background

Methods

Results

Publications

Remote ischemic preconditioning attenuates intestinal mucosal damage: insight from a rat model of ischemia-reperfusion injury.

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