Abstract 15498: Selective Inhibition of the Immunoproteasome Attenuates Adverse Left Ventricular Remodeling, Improves Cardiac Function, and Prevents Heart Failure After Myocardial Infarction
We have previously shown proteasome (Prot) activation after myocardial infarction (MI) in mice. Here we use pharmacologic inhibitors to discriminate between effects of constitutive and immunoproteasome (iProt) activation to test the hypothesis that the iProt mediates cardiac dysfunction after MI.
Methods/Results: Mice underwent permanent ligation of the left coronary artery or sham surgery. At 2 weeks, protein levels of β5i (a key iProt subunit) were increased by 70% (P<0.05) with no change in the constitutive β5 subunit, suggesting selective activation of the iProt. Using an assay (ProCISE) that measures active sites on β5 and β5i, we found a 30% increase in the β5i:β5 active site ratio after MI compared to sham. Mice were administered bortezomib (BZM, 0.2 mg/kg, IP daily), a non-selective Prot inhibitor, ONX 0914 (5 or 10 mg/kg, SC 3X/wk), a selective iProt inhibitor, or vehicle for 2 wks post-MI. Echocardiographic measurements at baseline and 2 wks were compared by 2-way RM ANOVA. BZM exacerbated adverse ventricular remodeling and systolic dysfunction compared to vehicle (Table). BZM also aggravated heart failure, as evidenced by higher lung weights and a higher E/E’la by echo (a measure highly correlated to left atrial pressure). In contrast, ONX 0914 (5 mg/kg) significantly decreased the β5i:β5 active site ratio (P<0.05) and attenuated ventricular remodeling, systolic dysfunction, and prevented heart failure (Table). ONX 0914 (10 mg/kg) had a neutral effect, probably owing to less selectivity for the iProt at the higher dose as measured by ProCISE.
Conclusions: After MI, non-selective Prot inhibition is detrimental, while selective inhibition of the iProt is highly protective. Inhibition of the iProt may prevent amplification of the inflammatory response to myocardial injury. These data establish the iProt as a viable target for intervention after MI, and possibly in other cardiac diseases associated with acute or chronic inflammation.
- © 2013 by American Heart Association, Inc.