TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice
Background. TNF-like weak inducer of apoptosis (TWEAK) has recently been shown to be potentially involved in adverse cardiac remodeling. However, neither the exact role of TWEAK itself nor of its receptor Fn14 in this setting is known. Aim of the Study. To analyze the effects of sTWEAK on myocardial...
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| Format: | Article |
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Wiley
2014-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2014/131950 |
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| author | Kai-Uwe Jarr Sabine Eschricht Linda C. Burkly Michael Preusch Hugo A. Katus Norbert Frey Emmanuel Chorianopoulos |
| author_facet | Kai-Uwe Jarr Sabine Eschricht Linda C. Burkly Michael Preusch Hugo A. Katus Norbert Frey Emmanuel Chorianopoulos |
| author_sort | Kai-Uwe Jarr |
| collection | DOAJ |
| description | Background. TNF-like weak inducer of apoptosis (TWEAK) has recently been shown to be potentially involved in adverse cardiac remodeling. However, neither the exact role of TWEAK itself nor of its receptor Fn14 in this setting is known. Aim of the Study. To analyze the effects of sTWEAK on myocardial function and gene expression in response to experimental myocardial infarction in mice. Results. TWEAK directly suppressed the expression of PGC-1α and genes of oxidative phosphorylation (OXPHOS) in cardiomyocytes. Systemic sTWEAK application after MI resulted in reduced left ventricular function and increased mortality without changes in interstitial fibrosis or infarct size. Molecular analysis revealed decreased phosphorylation of PI3K/Akt and ERK1/2 pathways associated with reduced expression of PGC-1α and PPARα. Likewise, expression of OXPHOS genes such as atp5O, cycs, cox5b, and ndufb5 was also reduced. Fn14 -/- mice showed significantly improved left ventricular function and PGC-1α levels after MI compared to their respective WT littermates (Fn14 +/+). Finally, inhibition of intrinsic TWEAK with anti-TWEAK antibodies resulted in improved left ventricular function and survival. Conclusions. TWEAK exerted maladaptive effects in mice after myocardial infarction most likely via direct effects on cardiomyocytes. Analysis of the potential mechanisms revealed that TWEAK reduced metabolic adaptations to increased cardiac workload by inhibition of PGC-1α. |
| format | Article |
| id | doaj-art-01bb9b6533b44a06ad5a27bd7969a13e |
| institution | OA Journals |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Wiley |
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| series | Mediators of Inflammation |
| spelling | doaj-art-01bb9b6533b44a06ad5a27bd7969a13e2025-08-20T02:01:49ZengWileyMediators of Inflammation0962-93511466-18612014-01-01201410.1155/2014/131950131950TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in MiceKai-Uwe Jarr0Sabine Eschricht1Linda C. Burkly2Michael Preusch3Hugo A. Katus4Norbert Frey5Emmanuel Chorianopoulos6Department of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyDepartment of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyDepartment of Immunology, Biogen Idec, Cambridge, MA 02142, USADepartment of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyDepartment of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyDepartment of Cardiology and Angiology, University of Kiel, Schittenhelmstraße 12, 24105 Kiel, GermanyDepartment of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanyBackground. TNF-like weak inducer of apoptosis (TWEAK) has recently been shown to be potentially involved in adverse cardiac remodeling. However, neither the exact role of TWEAK itself nor of its receptor Fn14 in this setting is known. Aim of the Study. To analyze the effects of sTWEAK on myocardial function and gene expression in response to experimental myocardial infarction in mice. Results. TWEAK directly suppressed the expression of PGC-1α and genes of oxidative phosphorylation (OXPHOS) in cardiomyocytes. Systemic sTWEAK application after MI resulted in reduced left ventricular function and increased mortality without changes in interstitial fibrosis or infarct size. Molecular analysis revealed decreased phosphorylation of PI3K/Akt and ERK1/2 pathways associated with reduced expression of PGC-1α and PPARα. Likewise, expression of OXPHOS genes such as atp5O, cycs, cox5b, and ndufb5 was also reduced. Fn14 -/- mice showed significantly improved left ventricular function and PGC-1α levels after MI compared to their respective WT littermates (Fn14 +/+). Finally, inhibition of intrinsic TWEAK with anti-TWEAK antibodies resulted in improved left ventricular function and survival. Conclusions. TWEAK exerted maladaptive effects in mice after myocardial infarction most likely via direct effects on cardiomyocytes. Analysis of the potential mechanisms revealed that TWEAK reduced metabolic adaptations to increased cardiac workload by inhibition of PGC-1α.http://dx.doi.org/10.1155/2014/131950 |
| spellingShingle | Kai-Uwe Jarr Sabine Eschricht Linda C. Burkly Michael Preusch Hugo A. Katus Norbert Frey Emmanuel Chorianopoulos TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice Mediators of Inflammation |
| title | TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice |
| title_full | TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice |
| title_fullStr | TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice |
| title_full_unstemmed | TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice |
| title_short | TNF-Like Weak Inducer of Apoptosis Aggravates Left Ventricular Dysfunction after Myocardial Infarction in Mice |
| title_sort | tnf like weak inducer of apoptosis aggravates left ventricular dysfunction after myocardial infarction in mice |
| url | http://dx.doi.org/10.1155/2014/131950 |
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