13260
2013
eng
4
108
article
1
2016-04-21
--
--
5-Lipoxygenase facilitates healing after myocardial infarction
Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{−/−}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{−/−}\) bone marrow in 5-LOX\(^{−/−}\) animals), indicating that an altered function of 5-LOX\(^{−/−}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{−/−}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{−/−}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function.
Basic Research in Cardiology
10.1007/s00395-013-0367-8
urn:nbn:de:bvb:20-opus-132602
Basic Research in Cardiology (2013) 108:367 DOI 10.1007/s00395-013-0367-8
Nadja Blömer
Christina Pachel
Urlich Hofmann
Peter Nordbeck
Wolfgang Bauer
Denise Mathes
Anna Frey
Barbara Bayer
Benjamin Vogel
Georg Ertl
eng
uncontrolled
lipoxygenase
eng
uncontrolled
myocardial infarction
eng
uncontrolled
extracellular matrix remodeling
eng
uncontrolled
inflammation
Krankheiten
open_access
Medizinische Klinik und Poliklinik I
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13260/143_Bloemer_Basics_Research_in_Cardiology.pdf
13469
2013
eng
1233–1244
34
article
1
2016-06-11
--
--
Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I
Aims: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism.
Methods and results: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the \([Ca^{2+}]_i\)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte \(Ca^{2+}_i\) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, \(Ca^{2+}_i\)-handling, and contractility via cGKI.
Conclusion: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte \(Ca^{2+}_i\) handling and contractility.
European Heart Journal
urn:nbn:de:bvb:20-opus-134693
European Heart Journal (2013) 34, 1233–1244 doi:10.1093/eurheartj/ehr445
Stefan Frantz
Michael Klaiber
Hideo A. Baba
Heinz Oberwinkler
Katharina Völker
Birgit Gaßner
Barbara Bayer
Marco Abeßer
Kai Schuh
Robert Feil
Franz Hofmann
Michaela Kuhn
eng
uncontrolled
cyclic
eng
uncontrolled
GMPcGMP-dependent protein kinase I
eng
uncontrolled
cardiac hypertrophy
eng
uncontrolled
natriuretic peptide
eng
uncontrolled
Ca2+i handling
Medizin und Gesundheit
open_access
Physiologisches Institut
Medizinische Klinik und Poliklinik I
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13469/146_Frantz_European_Heart.pdf
12988
2013
eng
e78938
11
8
article
1
2016-03-13
--
--
Exogenous Administration of a Recombinant Variant of TWEAK Impairs Healing after Myocardial Infarction by Aggravation of Inflammation
Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factorinducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined.
Methods and results: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality.
Conclusion: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium.
PLoS ONE
10.1371/journal.pone.0078938
urn:nbn:de:bvb:20-opus-129889
PLoS ONE 8(11): e78938. doi:10.1371/journal.pone.0078938
Christina Pachel
Denise Mathes
Barbara Bayer
Charlotte Dienesch
Gaby Wangorsch
Wolfram Heitzmann
Isabell Lang
Hossein Ardehali
Georg Ertl
Thomas Dandekar
Harald Wajant
Stefan Frantz
eng
uncontrolled
apoptosis
eng
uncontrolled
myocardial infarction
eng
uncontrolled
neutrophils
eng
uncontrolled
cytokines
eng
uncontrolled
inflammation
eng
uncontrolled
myocardium
eng
uncontrolled
heart
eng
uncontrolled
extracellular matrix
Medizin und Gesundheit
open_access
Medizinische Klinik und Poliklinik I
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12988/088_Exogenous Administration of a Recombinant Variant of.pdf
12876
2013
eng
56
11
article
1
2016-03-07
--
--
Mena/VASP and alphaII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy
Background: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks.
Results: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired.
Conclusions: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
Cell Communication and Signaling
10.1186/1478-811X-11-56
urn:nbn:de:bvb:20-opus-128760
Cell Communication and Signaling 2013, 11:56. doi:10.1186/1478-811X-11-56
311575
Peter M. Benz
Carla J. Merkel
Kristin Offner
Marco Abeßer
Melanie Ullrich
Tobias Fischer
Barbara Bayer
Helga Wagner
Stepan Gambaryan
Jeanine A. Ursitti
Ibrahim M. Adham
Wolfgang A. Linke
Stephan M. Feller
Ingrid Fleming
Thomas Renné
Stefan Frantz
Andreas Unger
Kai Schuh
eng
uncontrolled
Mena/VASP
eng
uncontrolled
dilated cardiomyopathy
eng
uncontrolled
actin
eng
uncontrolled
heart
eng
uncontrolled
spectrin
Physiologie und verwandte Themen
open_access
Medizinische Fakultät
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12876/016_Benz_Mena_VASP.pdf