Selective Inhibition of the Immunoproteasome β5i Prevents PTEN Degradation and Attenuates Cardiac Hypertrophy

Abstract

Cardiac hypertrophy without appropriate treatment eventually progresses to heart failure. Our recent data demonstrated that the immunoproteasome subunit b5i promotes cardiac hypertrophy. However, whether b5i is a promising therapeutic target for treating hypertrophic remodeling remains unknown. Here, we investigated the effects of PR-957, a b5i-specific inhibitor, on angiotensin II (Ang II)-induced hypertrophic remodeling in the murine heart. The infusion of Ang II increased immunoproteasome chymotrypsin-like activity and b5i catalytic subunit expression in the heart, whereas PR-957 treatment fully blocked the enhanced immunoproteasome activity caused by Ang II. Moreover, the administration of PR-957 significantly suppressed Ang II-induced cardiac hypertrophy, fibrosis, and inflammation. Mechanistically, PR-957 treatment inhibited phosphatase and tensin homolog on chromosome ten (PTEN) degradation, thereby inhibiting multiple signals including AKT/mTOR, ERK1/2, transforming growth factor-b, and IKB/NF-kB. Furthermore, PTEN blocking by its specific inhibitor VO-OHpic markedly attenuated the inhibitory effect of PR-957 on Ang II-induced cardiac hypertrophy in mice. We conclude that PR-957 blocks PTEN degradation and activates its downstream mediators, thereby attenuating Ang II-induced cardiac hypertrophy. These findings highlight that PR-957 may be a potential therapeutic agent for Ang II-induced hypertrophic remodeling.

Angiotensin II Induces Cardiac Edema and Hypertrophic Remodeling through Lymphatic-Dependent Mechanisms

“…To explain how Ang II induces lymphatic vessel permeability by reducing MKP5 and VE-cadherin protein levels and activating p38 MAPK, we measured proteasome activity and examined the levels of proteasome catalytic subunits in vivo and in vitro. Consistent with previous reports in CMs, endothelial cells, and other cell types from Ang II-infused mice [26,29,51], Ang II treatment also significantly upregulated the expression of the immunoproteasome subunits β2i and β5i and increased trypsin-like and chymotrypsin-like activity but downregulated MKP5 and VE-cadherin expression and activated p38 MAPK in the heart and LECs (Figures 1 and 5). Conversely, treatment of mouse LECs with losartan (an AT1R antagonist) or epoxomicin (a proteasome inhibitor) markedly reversed the Ang II-induced decreases in MKP5 and VEcadherin protein expression and the activation of p38 MAPK, leading to attenuation of lymphatic vessel hyperpermeability (Figures 5 and 6).…”

Deficiency of LMP10 Attenuates Diet-Induced Atherosclerosis by Inhibiting Macrophage Polarization and Inflammation in Apolipoprotein E Deficient Mice

“…In a mouse model of angiotensin II (Ang II)-induced cardiac remodeling, proteolytic activities and expression of the immunoproteasome subunits LMP2, LMP10, and LMP7 were found to be significantly up-regulated (Li et al, 2015). Genetic and pharmaceutical inactivation of LMP7 or LMP10 subunits is sufficient to elicit profound impacts on both ventricular hypertrophy and atrial fibrillation induced by Ang II infusion (Li et al, 2018(Li et al, , 2019Xie et al, 2019Xie et al, , 2020. In addition to pressure overload, immunoproteasomes are also involved in other cardiac diseases, such as doxorubicin-induced cardiotoxicity (Zhao et al, 2015) and deoxycorticosterone acetate (DOCA)/Saltinduced heart failure (Yan et al, 2017).…”

Blood Immunoproteasome Activity Is Regulated by Sex, Age and in Chronic Inflammatory Diseases: A First Population-Based Study

“…Immunoproteasome dysfunction is also a feature of cardiovascular diseases such as dilated cardiomyopathy, cardiac failure, and atherosclerosis and has been correlated with disease progression [ 31 , 32 ]. The use of immunoproteasome knockout mouse models and specific immunoproteasome inhibitors strongly suggest a causal role for the immunoproteasome for the development of cardiac hypertrophy, hypertensive cardiac remodeling, autoimmune-mediated myocarditis and atherosclerotic lesion formation [ 33 , 34 , 35 , 36 , 37 , 38 ]. In diabetes, impaired overall proteasome function has been observed in beta cells of the pancreas of type I diabetes patients and in experimental models [ 39 , 40 , 41 ].…”