PKCbII Inhibition in Heart Failure Figure 6. Impaired protein quality control in left ventricular remodeling and heart failure in humans. A. ATP-dependent and - independent proteasomal activity, B. oxidized protein levels (determined by Western blot) and C. polyubiquitinated protein levels (determined by Western blot) in biopsied hearts from aortic stenosis-induced left ventricular remodeling (LVR) patients (green bars), ischemic cardiomyopathy- induced heart failure patients (red bars) and autopsied non-failing human hearts (white bars). D. Negative correlation between proteasomal function and oxidized protein accumulation in failing (aortic stenosis-LVR and ischemic-HF) and non-failing heart samples. E. Total PKC levels in failing hearts compared to non-failing hearts and F. Representative blots of PKCbII and PKCa proteins in total and Triton-soluble fraction (particulate fraction) in biopsied hearts from aortic stenosis-induced left ventricular remodeling patients (n = 6, green bars) and ischemic cardiomyopathy-induced heart failure patients (n = 3, red bars) compared to autopsied non-failing human hearts (n = 6, trace). Total and Triton-soluble fractions were normalized against GAPDH and Gao, respectively. Error bars indicate SEM. *, p,0.05 compared to control (non-failing heart). 1, p,0.05 compared to aortic stenosis-LVR patients. doi:10.1371/journal.pone.0033175.g006 that aged hearts are more susceptible to UPS dysfunction and PQC disruption. Considering that proteasomal dysfunction is likely responsible for PQC disruption in HF, therapies that prevent or reverse selectively HF-induced proteasomal dysfunction may be of value for these patients. Our data in two models of HF in rats suggest that sustained inhibition of PKCbII may provide such novel treatment for HF, since selective inhibition of PKCbII with bIIV5- 3 appears safe, even after many weeks of treatment [9,11,17]. We showed in animal models that inhibition of PKCbII with bIIV5-3 treatment re-established cardiac PQC, and not only prevented further deterioration of cardiac function, but actually improved PLoS ONE | www.plosone.org 8 March 2012 | Volume 7 | Issue 3 | e33175