Abstract 8779: Effect of Cathepsin a Inhibition on Cardiac Function and Remodeling in Rats with Heart Failure Induced by Ischemia and Long-Term Reperfusion
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 SAR1 (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 TGFβ, 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 makes this enzyme a highly promising target for the treatment of post-MI heart failure patients. SAR1 has the potential to introduce a new treatment option for patients with acute MI to further preserve myocardial function on top of standard treatment.
- © 2011 by American Heart Association, Inc.