Clin Res Cardiol 101, Suppl 1, April 2012

P988 - Cathepsin A inhibition prevents the adverse remodeling outside the infarction area resulting in the preservation of myocardial function in rats with heart failure

T. Sadowski1, W. Linz1, S. Ruf1, T. Huebschle1, D. Linz2, G. Horstick3, P. Wohlfahrt1, H.-P. Juretschke1, C. Neumann-Haefelin1, A. Kannt1, H. Ruetten1

1Diabetes Division, Sanofi Aventis Deutschland GmbH, Frankfurt; 2Innere Medizin III, Kardiologie, Angiologie, intern. Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar; 3Klinik für Kardiologie und Angiologie, Evangelische Krankenhaus Oberhausen GmbH, Oberhausen;

Introduction: Cathepsin A (CathA) is a lysosomal carboxypeptidase involved in the cardiac metabolism of various peptide hormones. Its expression is significantly upregulated in the border zone after myocardial infarction (MI) in rats. Affymetrix profiling in MI patients revealed a similar regulation. Method: Male Wistar rats were randomized in: (1) Sham-OP, (2) I/R-Placebo (I/R=30min ischemia/reperfusion of the left coronary artery), (3) I/R-ramipril (RA 1 mg/kg/d p.o.), (4) I/R - CathA Inhibitor SAR164653 (SAR1 30 mg/kg/d p.o.). After 9 weeks of treatment a magnetic resonance imaging (MRI)-investigation was done. Thereafter, left ventricles (LV) were fixed for histological evaluation and gene expression analysis by Taqman PCR. Brain natriuretic peptide (BNP) was measured in serum by ELISA. Results: Inhibition of CathA with SAR1 attenuated left ventricular (LV) remodeling observed after I/R without altering blood pressure. MRI analysis revealed preserved ventricular wall geometry in infarcted and non-infarcted regions. Global parameters such as ejection fraction, cardiac output, stroke volume, end-diastolic volume, end-systolic volume and left ventricle peak filling rate were significantly improved during dobutamin stress when compared to placebo treated I/R-rats. Especially the regional parameters such as wall motion and systolic wall thickness were improved in the infarcted area and even normalized in the non-infarcted area in SAR-treated I/R-rats. In contrast, RA treatment did not prevent the adverse remodeling. In all parameters SAR1 was clearly superior to RA. Histological investigations confirmed the beneficial effects of SAR1 treatment and serum levels of BNP were significantly reduced in SAR1 treated animals. LV gene expression of TGFb, ANP, collagen type III and CD14 was decreased by ramipril and SAR1 treatment. Conclusion: We identified hitherto unknown functions of CathA in cardiac disease. Especially the dramatic improvement in LV wall geometry after inhibition of CathA with SAR1 dedicates this enzyme as a highly promising target for the treatment of post-MI heart failure patients. SAR1 has the potential to introduce a new treatment option in patients with acute MI to further preserve myocardial function on top of standard treatment.

Clin Res Cardiol 101, Suppl 1, April 2012 Zitierung mit Vortrags- oder Posternummer s.o. DOI 10.1007/s00392-012-1100-6

http://www.abstractserver.de/dgk2012/ft/abstracts/P988.htm