Ablation and Inhibition of the Immunoproteasome Catalytic Subunit LMP7 Attenuate Experimental Abdominal Aortic Aneurysm Formation in Mice

Abstract

Low–molecular mass protein 7 (LMP7) is a proteolytic subunit of the immunoproteasome that is involved in regulating inflammatory responses. However, the role of LMP7 in the pathogenesis of abdominal aortic aneurysm (AAA) remains unknown. In this study, ApoE knockout (KO) or LMP7/ApoE double KO (dKO) mice were infused with angiotensin II (Ang II, 1000 ng/kg per minute) for up to 28 d. We found that LMP7 expression was significantly upregulated in AAA tissues from ApoE KO mice and human patients. Moreover, Ang II infusion markedly increased the incidence and severity of AAA in ApoE KO mice, which was considerably reduced in LMP7/ApoE dKO mice. Histological alterations, including aortic wall thickening, collagen deposition, elastin fragmentation, and vascular smooth muscle cell apoptosis in AAA tissue of ApoE KO mice, were also significantly attenuated in LMP7/ApoE dKO mice. Interestingly, LMP7/ApoE dKO mice showed a marked reduction of infiltration of CD3+ T cells, especially CD4+ T cells in AAA tissues compared with ApoE KO mice. Moreover, ablation of LMP7 substantially inhibited the differentiation of CD4+ T cells into Th1 and Th17 cells by reducing the activation of multiple transcriptional factors. We also investigated the effects of an LMP7-specific inhibitor PR-957 (also known as ONX 0914) on AAA formation in ApoE KO mice. PR-957 treatment could reduce the AAA incidence and severity. In conclusion, our results provide, to our knowledge, novel evidence that ablation or pharmacological inhibition of LMP7 attenuates Ang II–induced AAA formation, and LMP7 might be a novel therapeutic target for treating AAA in humans.

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

“…Previous studies have indicated that the immunoproteasomes play an important role in apoptosis in cancers, partially through regulating oxidative and ER stress [45][46][47]. Recently, we found that β5i inactivation attenuated SMC apoptosis in angiotensin II-induced aneurysm in eKO mice [48]. Here, we further demonstrated that both genetic deletion and pharmacological inhibition of β5i blunted apoptotic cell accumulation in diet-induced atherosclerosis through suppression of efferocytosis.…”

Gallic Acid Attenuates Angiotensin II-Induced Hypertension and Vascular Dysfunction by Inhibiting the Degradation of Endothelial Nitric Oxide Synthase

“…The depletion of β2i or β5i markedly attenuates Ang II-induced blood pressure, cardiac hypertrophy, and atrial fibrillation in mice ( Li et al., 2015 ; Li et al., 2018 ; Li J. et al, 2019 ). Furthermore, we revealed that β5i is involved in the modulation of the infiltration of proinflammatory cells into abdominal aortic aneurysm and atherosclerotic lesion, as well as vascular remodeling in ApoE knockout mice ( Li F. D. et al, 2019 ; Wang et al., 2020 ). It is worth noting that several nutritional factors, such as quercetin, δ-tocotrienol, and resveratrol, are potential proteasome inhibitors, which may represent a strategy for treating cardiovascular diseases ( Qureshi et al., 2013 ; Chen et al., 2019 ).…”

“…Previous studies revealed that adverse stimuli activate the immunoproteasome, which is involved in the pathogenesis of cardiovascular diseases including cardiac hypertrophy, ischemia-reperfusion injury, and neointimal formation ( Barringhaus and Matsumura, 2007 ; Li et al., 2015 ; Guo et al., 2016 ; Chen et al., 2019 ). Importantly, our recent studies indicate that Ang II infusion upregulates the activity and expression of immunoproteasome subunits (β2i and β5i) in the heart, atria, retina, and aorta ( Li et al., 2015 ; Li et al., 2018 ; Wang et al., 2018 ; Li F. D. et al, 2019 ; Li J. et al, 2019 ; Wang et al., 2020 ). The depletion of β2i or β5i markedly attenuates Ang II-induced blood pressure, cardiac hypertrophy, and atrial fibrillation in mice ( Li et al., 2015 ; Li et al., 2018 ; Li J. et al, 2019 ).…”

Deficiency of the Immunoproteasome LMP10 Subunit Attenuates Angiotensin II-Induced Cardiac Hypertrophic Remodeling via Autophagic Degradation of gp130 and IGF1R

“…Recently, we reported that the immunoproteasome is involved in the regulation of several cardiovascular diseases. The functional roles of LMP7 in cardiac hypertrophy, atrial fibrillation, abdominal aortic aneurysm, and retinopathy have been investigated extensively (Li F. D. et al, 2019;Li J. et al, 2019;Xie et al, 2019;Wang et al, 2020). Meanwhile, we found that LMP10 (β2i) plays a critical role in DOCA-salt-induced myocardial fibrosis and high-dose Ang II-induced atrial fibrillation and retinopathy (Yan et al, 2017;Li J. et al, 2018;Wang S. et al, 2018).…”

“…In contrast, blockage of proteasome activity using an inhibitor represses cardiac hypertrophy (Li N. et al, 2015). Recently, we demonstrated that the upregulation of LMP7 contributes to the development of several cardiovascular diseases, including pressure overloadinduced cardiac hypertrophy, Ang II-induced atrial fibrillation, abdominal aortic aneurysm, and retinopathy (Li F. D. et al, 2019;Li J. et al, 2019;Xie et al, 2019). Moreover, LMP10 plays a critical role in DOCA-salt-induced myocardial fibrosis (Yan et al, 2017); however, the role of LMP10 in the development of Ang II-induced cardiac hypertrophic remodeling remains unclear.…”