TY  - JOUR
A1  - Popp, Sandy
A1  - Schmitt-Böhrer, Angelika
A1  - Langer, Simon
A1  - Hofmann, Ulrich
A1  - Hommers, Leif
A1  - Schuh, Kai
A1  - Frantz, Stefan
A1  - Lesch, Klaus-Peter
A1  - Frey, Anna
T1  - 5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction
JF  - Journal of Clinical Medicine
N2  - Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally naïve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (−/−) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT−/− mice with infarct sizes >30% experienced 100% mortality, while 50% of 5-HTT+/− and 37% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30%) 5-HTT−/− mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT−/− mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.
KW  - chronic heart failure
KW  - myocardial infarction
KW  - serotonin transporter deficient mice
KW  - anxiety
KW  - depression
KW  - behavior
KW  - inflammation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242739
SN  - 2077-0383
VL  - 10
IS  - 14
ER  - 
TY  - JOUR
A1  - Korb, Doreen
A1  - Tng, Priscilla Y.
A1  - Milenkovic, Vladimir M.
A1  - Reichhart, Nadine
A1  - Strauss, Olaf
A1  - Ritter, Oliver
A1  - Fischer, Tobias
A1  - Benz, Peter M.
A1  - Schuh, Kai
T1  - Identification of PDZ domain containing proteins interacting with \(Ca_v1.2\) and PMCA4b
JF  - ISRN Cell Biology
N2  - PDZ (PSD-95/Disc large/Zonula occludens-1) protein interaction domains bind to cytoplasmic protein C-termini of transmembrane proteins. In order to identify new interaction partners of the voltage-gated L-type \(Ca^{2+}\) channel Cav1.2 and the plasma membrane \(Ca^{2+}\) ATPase 4b (PMCA4b), we used PDZ domain arrays probing for 124 PDZ domains. We confirmed this byGST pulldowns and immunoprecipitations. In PDZ arrays, strongest interactionswith \(Ca_v1.2\) and PMCA4b were found for the PDZ domains of SAP-102, MAST-205, MAGI-1, MAGI-2, MAGI-3, and ZO-1. We observed binding of the \(Ca_v1.2\) C-terminus to PDZ domains of NHERF1/2, Mint-2, and CASK. PMCA4b was observed to interact with Mint-2 and its known interactions with Chapsyn-110 and CASK were confirmed. Furthermore, we validated interaction of \(Ca_v1.2\) and PMCA4b with NHERF1/2, CASK,MAST-205 and MAGI-3 viaimmunoprecipitation. We also verified the interaction of \(Ca_v1.2\) and nNOS and hypothesized that nNOS overexpression might reduce \(Ca^{2+}\) influx through \(Ca_v1.2\). To address this, we measured \(Ca^{2+}\) currents in HEK 293 cells co-expressing \(Ca_v1.2\) and nNOS and observed reduced voltage-dependent \(Ca_v1.2\) activation. Taken together, we conclude that \(Ca_v1.2\) and PMCA4b bind promiscuously to various PDZ domains, and that our data provides the basis for further investigation of the physiological consequences of these interactions.
KW  - Cell
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130585
IS  - Article ID 265182
ER  - 
TY  - JOUR
A1  - Frantz, Stefan
A1  - Klaiber, Michael
A1  - Baba, Hideo A.
A1  - Oberwinkler, Heinz
A1  - Völker, Katharina
A1  - Gaßner, Birgit
A1  - Bayer, Barbara
A1  - Abeßer, Marco
A1  - Schuh, Kai
A1  - Feil, Robert
A1  - Hofmann, Franz
A1  - Kuhn, Michaela
T1  - Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I
JF  - European Heart Journal
N2  - 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.
KW  - cyclic
KW  - GMPcGMP-dependent protein kinase I
KW  - cardiac hypertrophy
KW  - natriuretic peptide
KW  - Ca2+i handling
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134693
VL  - 34
ER  -