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Lauer, Dilyara; Slavic, Svetlana; Sommerfeld, Manuela; Thöne-Reineke, Christa; Sharkovska, Yuliya; Hallberg, Anders; Dahlöf, Bjorn; Kintscher, Ulrich; Unger, Thomas; Steckelings, Ulrike Muscha; Kaschina, Elena; Kaschina, Elena

Abstract 58: AT2 Receptor Agonism Regulates TIMP1/MMP9 Axis in the Heart Preventing Cardiac Fibrosis and Improving Heart Function After Experimental Myocardial Infarction

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  • Medientyp: E-Artikel
  • Titel: Abstract 58: AT2 Receptor Agonism Regulates TIMP1/MMP9 Axis in the Heart Preventing Cardiac Fibrosis and Improving Heart Function After Experimental Myocardial Infarction
  • Beteiligte: Lauer, Dilyara; Slavic, Svetlana; Sommerfeld, Manuela; Thöne-Reineke, Christa; Sharkovska, Yuliya; Hallberg, Anders; Dahlöf, Bjorn; Kintscher, Ulrich; Unger, Thomas; Steckelings, Ulrike Muscha; Kaschina, Elena; Kaschina, Elena
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2013
  • Erschienen in: Hypertension
  • Sprache: Englisch
  • DOI: 10.1161/hyp.62.suppl_1.a58
  • ISSN: 0194-911X; 1524-4563
  • Schlagwörter: Internal Medicine
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p> <jats:bold>Aims:</jats:bold> A selective nonpeptide agonist for the angiotensin AT2 receptor compound 21 (C21) improved cardiac functions 7 days after myocardial infarction (MI). Here, we aimed to investigate what are the cellular mechanisms underlying cardiac protection in the late stage after MI. </jats:p> <jats:p> <jats:bold>Methods and Results:</jats:bold> MI was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.03mg/kg i.p. daily) started 6h after MI and continued for 6 weeks. Hemodynamic parameters were measured via transthoracic Doppler echocardiography and intracardiac Samba catheter. The expression of MMP9, TIMP1, TGF-β1 and collagen content were determined in left ventricle. Anti-proteolytic effects were additionally studied in primary cardiac fibroblasts. </jats:p> <jats:p> C21 significantly improved systolic and diastolic function 6 weeks after MI in comparison with the vehicle group as shown by ejection fraction (71.2±4.7 % vs. 53.4±7.0%; p&lt;0.001), fractional shortening (40.8±2.3% vs. 30.9±3.1%; p&lt;0.05), LVIDs (4.4±0.5mm vs. 5.2±0.8mm; p&lt;0.05), LV EDP (16.9±1.2mmHg vs. 22.1±1.4mmHg; p&lt;0.05), E/A ratio, dP/dt <jats:sub>max</jats:sub> and dP/dt <jats:sub>min</jats:sub> (p&lt;0.05). Moreover, C21 improved arterial stiffness parameter (AIx) (18±1.2% vs. 25%±1.8, p&lt;0.05) and reduced collagen content (15%; p&lt;0.05) in postinfarcted myocardium. TIMP1 protein expression in the left ventricle was strongly up-regulated (17.7-fold; p&lt;0.05) whereas MMP9 and TGF-β1 were significantly down-regulated (1.5-fold, p&lt;0.05; 3.4-fold p&lt;0.001, respectively) in the treated group. In cardiac fibroblasts, C21 primarily induced TIMP1 expression followed by attenuated MMP9 secretion and TGF-β1 down-regulation. </jats:p> <jats:p> <jats:bold>Conclusion:</jats:bold> C21 improves heart function in the late stage after MI and prevents cardiac remodeling. Activation of TIMP1 and subsequent inhibition of MMP9-mediated proteolysis as well as down-regulation of TGF-β1 followed by decreased collagen accumulation may attenuate disintegration of the extracellular matrix and reduce fibrosis. </jats:p>
  • Zugangsstatus: Freier Zugang