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Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury.

ABSTRACT: We have demonstrated that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), a scaffolding protein common to TNF receptors 1 and 2, confers cytoprotection in the heart. However, the mechanisms for the cytoprotective effects of TRAF2 are not known.Mice with cardiac-restricted overexpression of low levels of TRAF2 (MHC-TRAF2LC) and a dominant negative TRAF2 (MHC-TRAF2DN) were subjected to ischemia (30-minute) reperfusion (60-minute) injury (I/R), using a Langendorff apparatus. MHC-TRAF2LC mice were protected against I/R injury as shown by a significant ?27% greater left ventricular (LV) developed pressure after I/R, whereas mice with impaired TRAF2 signaling had a significantly ?38% lower LV developed pressure, a ?41% greater creatine kinase (CK) release, and ?52% greater Evans blue dye uptake after I/R, compared to LM. Transcriptional profiling of MHC-TRAF2LC and MHC-TRAF2DN mice identified a calcium-triggered exocytotic membrane repair protein, dysferlin, as a potential cytoprotective gene responsible for the cytoprotective effects of TRAF2. Mice lacking dysferlin had a significant ?39% lower LV developed pressure, a ?20% greater CK release, and ?29% greater Evans blue dye uptake after I/R, compared to wild-type mice, thus phenocopying the response to tissue injury in the MHC-TRAF2DN mice. Moreover, breeding MHC-TRAF2LC onto a dysferlin-null background significantly attenuated the cytoprotective effects of TRAF2 after I/R injury.The study shows that dysferlin, a calcium-triggered exocytotic membrane repair protein, is required for the cytoprotective effects of TRAF2-mediated signaling after I/R injury.

SUBMITTER: Tzeng HP

PROVIDER: S-EPMC3959693 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury.

Tzeng Huei-Ping HP Evans Sarah S Gao Feng F Chambers Kari K Topkara Veli K VK Sivasubramanian Natarajan N Barger Philip M PM Mann Douglas L DL

Journal of the American Heart Association 20140226 1

<h4>Background</h4>We have demonstrated that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), a scaffolding protein common to TNF receptors 1 and 2, confers cytoprotection in the heart. However, the mechanisms for the cytoprotective effects of TRAF2 are not known.<h4>Methods/results</h4>Mice with cardiac-restricted overexpression of low levels of TRAF2 (MHC-TRAF2LC) and a dominant negative TRAF2 (MHC-TRAF2DN) were subjected to ischemia (30-minute) reperfusion (60-minute) injury ...[more]

PMID: 24572254

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Project description:Lixisenatide is a glucagon-like peptide-1 analog which stimulates insulin secretion and inhibits glucagon secretion and gastric emptying. We investigated cardioprotective effects of lixisenatide in rodent models reflecting the clinical situation.The acute cardiac effects of lixisenatide were investigated in isolated rat hearts subjected to brief ischemia and reperfusion. Effects of chronic treatment with lixisenatide on cardiac function were assessed in a modified rat heart failure model after only transient coronary occlusion followed by long-term reperfusion. Freshly isolated cardiomyocytes were used to investigate cell-type specific mechanisms of lixisenatide action.In the acute setting of ischemia-reperfusion, lixisenatide reduced the infarct-size/area at risk by 36% ratio without changes on coronary flow, left-ventricular pressure and heart rate. Treatment with lixisenatide for 10 weeks, starting after cardiac ischemia and reperfusion, improved left ventricular end-diastolic pressure and relaxation time and prevented lung congestion in comparison to placebo. No anti-fibrotic effect was observed. Gene expression analysis revealed a change in remodeling genes comparable to the ACE inhibitor ramipril. In isolated cardiomyocytes lixisenatide reduced apoptosis and increased fractional shortening. Glucagon-like peptide-1 receptor (GLP1R) mRNA expression could not be detected in rat heart samples or isolated cardiomyocytes. Surprisingly, cardiomyocytes isolated from GLP-1 receptor knockout mice still responded to lixisenatide.In rodent models, lixisenatide reduced in an acute setting infarct-size and improved cardiac function when administered long-term after ischemia-reperfusion injury. GLP-1 receptor independent mechanisms contribute to the described cardioprotective effect of lixisenatide. Based in part on these preclinical findings patients with cardiac dysfunction are currently being recruited for a randomized, double-blind, placebo-controlled, multicenter study with lixisenatide.(ELIXA, ClinicalTrials.gov Identifier: NCT01147250).

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Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury.

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Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury.

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