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Fakultät für Medizin

Institut für Pharmakologie
und Toxikologie

Direktor:
Prof. Dr. Dr. Stefan Engelhardt

Biedersteiner Str. 29
80802 München
Tel.: +49-89-4140-3260
pharma(at)ipt.med.tum.de

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Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis

(May 2016) Fibrosis is marked by excessive deposition of extracellular matrix and uncontrolled formation of connective tissue, both leading to morphologic changes that impair heart function. In a study published in the undefinedJournal of the American College of Cardiology Kathleen Meyer et al. (Sarikas laboratory) identified non-age-related premature senescence of myofibroblasts as novel anti-fibrotic mechanism in the heart. By using different animal models of cardiac diseases, together with human heart biopsies, the authors showed that myofibroblasts undergo premature senescence in the course of fibrogenesis. Genetic inactivation of the cellular senescence program resulted in aggravated fibrosis and cardiac dysfunction. In contrast, heart-specific induction of senescence limited fibrosis and had cardioprotective effects. Collectively, this study establishes premature senescence of myofibroblasts as essential anti-fibrotic mechanism and potential therapeutic target in myocardial fibrosis.  

For further information please contact PD Dr. Antonio Sarikas (antonio.sarikas(at)tum.de)

Use of Learning Media by Undergraduate Medical Students in Pharmacology: A Prospective Cohort Study

(April 2015) In a study published in the current issue of PLOS ONE, Joanna Gutmann (AG Dr. Sarikas) provides a comprehensive assessment of learning media use by undergraduate medical students in pharmacology. Using a prospective mixed-method design with daily online surveys and final semi-structured interviews, the authors demonstrate a preponderance of digital resources for learning by both male and female students in pharmacology. Ms Gutmann and co-workers show that students employ a broad spectrum of learning media, of which lecture slides, apps and personal notes were most utilized, followed by textbooks (> 300 pages), internet search and e-learning cases. Finally, the results of this study indicate that students`use of some learning resources is dynamic and varies between teaching and self-study periods.

Interhelical interaction and phosphorylation regulate activation kinetics of different beta1-adrenoceptor variants

(January 2015) In a study published in The Journal of Biological Chemistry we analyzed the mechanism underlying the higher efficacy of the Arg389 variant of the human beta1-adrenoceptor (ADRB1; p.Arg389Gly representing the most common polymorphism within the human ADRB1). Despite its hyperfunctionality, we found the Arg389 variant to be hyperphosphorylated upon continuous stimulation with norepinephrine compared with the Gly389 variant. Using ADRB1 sensors to monitor activation kinetics by fluorescence resonance energy transfer, Arg389-ADRB1 exerted faster activation speed and arrestin recruitment than the Gly389 variant. Both depended on phosphorylation of the receptor. Furthermore, structural modeling of the human beta1-adrenoceptor followed by site-directed mutagenesis revealed that interaction of the side chain of Arg389 (located in helix 8) with opposing amino acid residues in helix 1 determined ADRB1 activation. Taken together, these findings indicate that differences in interhelical interaction regulate the different activation speed and efficacy of the beta1-adrenoceptor as a prototypical G protein-coupled receptor.
undefinedMore Information

 

Ahles A, Rodewald F, Rochais F, Bünemann M and Engelhardt S. J Biol Chem. 2015 Jan 16;290(3):1760-9. doi: 10.1074/jbc.M114.607333.

Cardiac myocyte-secreted cAMP exerts paracrine action via adenosine receptor activation

(December 2014) In a study published in The Journal of Clinical Investigation we investigated whether cAMP extruded from cardiomyocytes (CM) may act as a signalling molecule in the cardiac interstitium. We found that infusion of cAMP into mice averted myocardial hypertrophy and fibrosis in a disease model of cardiac pressure overload. The protective effect of exogenous cAMP required adenosine receptor signaling. We next observed that extracellular cAMP blocked the βAR-mediated increase in intracellular cAMP in cardiomyocytes by activating the A1 adenosine receptors. In contrast, application of extracellular cAMP onto cardiac fibroblasts induced an increase in intracellular cAMP levels through the A2 adenosine receptors. FRET-based imaging of cAMP formation in primary cells and in myocardial tissue from murine hearts revealed a paracrine role for secreted cAMP in intercellular signaling in the myocardium. Our data demonstrate that β-adrenergic stimulation causes cardiomyocytes to secrete cAMP as a source of adenosine, which then signals to cardiac fibroblasts (preventing fibrosis) and to vicinal cardiomyocytes (preventing hypertrophy). While our study details this mechanism in an exemplary way for the myocardium, we postulate it to be of broader relevance in other tissues.

 

 

Sassi Y, Ahles A, Truong DJF, Baqi Y, Lee SY, Husse B, Hulot JS, Foinquinos A, Thum T, Müller CE, Dendorfer A, Laggerbauer B, Engelhardt S. J Clin Invest. 2014 Dec; 124(12): 5385-97