Abstract 302: Cathepsin D Haploinsufficiency Exacerbates Post Myocardial Infarction Cardiac Remodeling and Malfunction by Impairing Autophagosome Removal

Abstract

Background: A marked decrease in the protein level and activity of cathepsin D (Ctsd), a major lysosomal protease, has been observed in failing human hearts; however, the pathophysiological significance of Ctsd downregulation in the heart remains undefined. Given the increasingly recognized role of the autophagic-lysosomal pathway in cardiac pathobiology, we sought to determine the impact of Ctsd haploinsufficiency on post myocardial infarction (MI) cardiac remodeling and explore the underlying mechanism. Methods and Results: MI was induced in 2-3 months old mixed-sex wild type (WT) or heterozygous Ctsd knockout (Ctsd +/- ) mice via permanent ligation of the left anterior descending (LAD) coronary artery. Myocardial Ctsd protein levels are reduced by ~50% in Ctsd +/- mice, compared with WT mice. Echocardiography (Echo) did not detect discernible difference between Ctsd +/- and WT mice immediately before and 1 week (wk) after MI; however, compared with the WT MI group, significantly greater left ventricular (LV) internal diameters at end systole and at end diastole and significantly smaller ejection fraction and fractional shortening were detected in the Ctsd +/- MI group at 2, 3, and 4 wks post-MI (p<0.05 ~ 0.001). LV pressure-volume relationship analyses at 4 wks post-MI also revealed that LV maximum and minimum dP/dt values were significantly reduced in the WT MI group, compared with the WT sham control group (p<0.05, 0.01); these post-MI reductions were more pronounced in the Ctsd +/- MI group (P<0.05, 0.01). The infarct size at 4 wks post-MI measured with trichrome staining was significantly enlarged by Ctsd +/- (p<0.002). These results indicate that Ctsd haploinsufficiency exacerbates post-MI cardiac remodeling and malfunction. Post-MI myocardial Ctsd protein levels were increased in WT mice but this increase was not detectable in Ctsd +/- mice. However, the myocardial protein levels of LC3-II, beclin1, and Atg5 were further elevated in Ctsd +/- MI mice, compared with the WT MI mice, indicative of impairment of autophagic flux in Ctsd +/- MI mice. Conclusion: Ctsd haploinsufficiency exacerbates maladaptive post-MI cardiac remodeling and malfunction likely through impairing autophagosome removal.