The immunoproteasome subunit LMP10 mediates angiotensin II-induced retinopathy in mice

Abstract

Inflammation has been implicated in a variety of retinal diseases. The immunoproteasome plays a critical role in controlling inflammatory responses, but whether activation of immunoproteasome contributes to angiotensin II (Ang II)-induced retinopathy remains unclear. Hypertensive retinopathy (HR) was induced by infusion of Ang II (3000 ng/kg/min) in wild-type (WT) and immunoproteasome subunit LMP10 knockout (KO) mice for 3 weeks. Changes in retinal morphology, vascular permeability, superoxide production and inflammation were examined by pathological staining. Our results showed that immunoproteasome subunit LMP10 expression and its trypsin-like activity were significantly upregulated in the retinas and serum of Ang II-infused mice and in the serum from patients with hypertensive retinopathy. Moreover, Ang II-infused WT mice showed an increase in the central retinal thickness, vascular permeability, reactive oxygen species (ROS) production and inflammation compared with saline controls, and these effects were significantly attenuated in LMP10 KO mice, but were aggravated in mice intravitreally injected with rAAV2-LMP10. Interestingly, administration of IKKβ specific inhibitor IMD-0354 remarkably blocked an Ang II-induced increase in vascular permeability, oxidative stress and inflammation during retinopathy. Mechanistically, Ang II-induced upregulation of LMP10 promoted PTEN degradation and activation of AKT/IKK signaling, which induced IkBα phosphorylation and subsequent degradation ultimately leading to activation of NF-kB target genes in retinopathy. Therefore, this study provided novel evidence demonstrating that LMP10 is a positive regulator of NF-kB signaling, which contributes to Ang II-induced retinopathy. Strategies for inhibiting LMP10 or IKKβ activity in the eye could serve as a novel therapeutic target for treating hypertensive retinopathy.

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

“…The immunoproteasome has critical functions in the regulation of protein degradation, immune cell homeostasis, oxidative stress and cell apoptosis [13,14]. Recently, we showed that the β2i and β5i subunits are involved in the development of cardiac remodeling, atrial fibrillation and retinopathy, thus extending previous knowledge about the immunoproteasome [15][16][17][18]. Notably, subunit β5i was upregulated in the shoulder areas of symptomatic carotid plaques as compared with non-symptomatic plaques, suggesting a correlation between β5i activity and plaque instability [19].…”

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

“…The regulatory effects of LMP10 on IκBα/NF-κB activation and signaling has further been confirmed in hypertensive atrial fibrillation and retinopathy (Li et al, 2018;Wang et al, 2018). In these two models, LMP10 promoted PTEN degradation and subsequent AKT1 activation, which then stimulated IKKβ-mediated IκBα phosphorylation and degradation, ultimately facilitating activation of NF-κB pathway (Li et al, 2018;Wang et al, 2018). Importantly, blocking NF-κB activation by administration of IKKβ specific inhibitor IMD-0354 remarkably blunted inflammation and disease phenotypes (Li et al, 2018;Wang et al, 2018).…”

“…For example, in Ang IIinduced cardiac hypertrophy, activation of immunoproteasomes was found to promote degradation of MKP-1 and IκBα and subsequent activation of STAT1 and NF-κB, thereby leading to Th1 cell differentiation and cardiac remodeling (Qin et al, 2018); while in DOCA/salt-induced cardiac hypertrophy, the immunoproteasome LMP10 subunit was shown to activate IκBα/ NF-κB and TGF-β1/Smad2/3 signaling to facilitate cardiac fibrosis and inflammation (Yan et al, 2017). The regulatory effects of LMP10 on IκBα/NF-κB activation and signaling has further been confirmed in hypertensive atrial fibrillation and retinopathy (Li et al, 2018;Wang et al, 2018). In these two models, LMP10 promoted PTEN degradation and subsequent AKT1 activation, which then stimulated IKKβ-mediated IκBα phosphorylation and degradation, ultimately facilitating activation of NF-κB pathway (Li et al, 2018;Wang et al, 2018).…”

Resveratrol as a new inhibitor of immunoproteasome prevents PTEN degradation and attenuates cardiac hypertrophy after pressure overload

“…Measurement of proteasome activity in the hearts was performed using fluorogenic peptide substrates, including caspase-like activity with Z-LLE-AMC (45 μmol/L), trypsin-like activity with Ac-RLR-AMC(40 μmol/L), and chymotrypsin-like activity with Suc-LLVY-AMC (18 μmol/L) as described [12] , [13] , [23] , [29] .…”

“…We recently reported that knockout of immunosubunit β2i reduced hypertension and cardiac fibrosis in DOCA (deoxycortone acetate)/salt mouse model [11] . Furthermore, β2i deletion attenuated Ang II-induced atrial inflammation, vascular permeability, fibrosis and atrial fibrillation [12] , [13] . These results suggest that immunoproteasome plays a role in cardiac diseases, and strategies aimed at inhibiting immunoproteasome activity may offer novel and effective therapeutic approaches to prevent these diseases.…”