The immunoproteasome catalytic β5i subunit regulates cardiac hypertrophy by targeting the autophagy protein ATG5 for degradation

Abstract

Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. The immunoproteasome is an inducible form of the proteasome that is intimately involved in inflammatory diseases. Here, we found that the expression and activity of immunoproteasome catalytic subunit β5i were significantly up-regulated in angiotensin II (Ang II)–treated cardiomyocytes and in the hypertrophic hearts. Knockout of β5i in cardiomyocytes and mice markedly attenuated the hypertrophic response, and this effect was aggravated by β5i overexpression in cardiomyocytes and transgenic mice. Mechanistically, β5i interacted with and promoted ATG5 degradation thereby leading to inhibition of autophagy and cardiac hypertrophy. Further, knockdown of ATG5 or inhibition of autophagy reversed the β5i knockout-mediated reduction of cardiomyocyte hypertrophy induced by Ang II or pressure overload. Together, this study identifies a novel role for β5i in the regulation of cardiac hypertrophy. The inhibition of β5i activity may provide a new therapeutic approach for hypertrophic diseases.

Immunoproteasome subunit β5i regulates diet‐induced atherosclerosis through altering MERTK‐mediated efferocytosis in Apoe knockout mice

“…Increasing studies indicate that inhibition of the β5i subunit by PR-957 is promising for the treatment of inflammatory and autoimmune diseases, with limited side effects [18,[53][54][55][56]. Here we extended the therapeutic potential of PR-957 and immunoproteasome inhibition in atherosclerosis; however, this needs further verification in other animal models.…”

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).…”

The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor

“…The heart was fixed in 4% paraformaldehyde solution for 24 hours and then embedded in paraffin. The sections (4 m) were stained with hematoxylin and eosin (H&E) and Masson's trichrome staining using the standard procedure (40,44). To assess myocyte size, heart sections were stained with tetramethyl rhodamine isothiocyanate (TRITC)-labeled wheat germ agglutinin [WGA; 50 g/ml in 1 × phosphate-buffered saline (PBS)] for 1 hour.…”

“…Heart tissues were fixed in neutral buffered formalin solution, embedded in paraffin, and then cut into 5-m serial sections. Immunohistochemistry staining was performed as described previously (44). Monoclonal antibody UCHL1 (1:100 dilution) and BNP (1:100 dilution) were used as primary antibodies.…”