ONX0914 inhibition of immunoproteasome subunit LMP7 ameliorates diabetic cardiomyopathy via restraining endothelial-mesenchymal transition
Clinical science (London, England : 1979)(2023)
摘要
Diabetic cardiomyopathy (DCM) is a chronic metabolic disease with few effective therapeu-tic options. Immunoproteasome is an inducible proteasome that plays an important role in the regulation of many cardiovascular diseases, while its role in DCM remains under discussion. The present study aims to demonstrate whether inhibiting immunoproteasome subunit low molecular weight polypeptide 7 (LMP7) could alleviate DCM. Here, we estab-lished a type I diabetes mellitus mouse model by streptozotocin (STZ) in 8-week-old male wild-type C57BL/6J mice. We found that immunoproteasome subunit LMP7 was overex-pressed in the heart of diabetic mice, while inhibiting LMP7 with pharmacological inhibitor ONX0914 significantly alleviated myocardial fibrosis and improved cardiac function. Be-sides, compared with diabetic mice, ONX0914 treatment reduced protein levels of mes-enchymal markers (Vimentin, & alpha;-smooth muscle actin, and SM22 & alpha;) and increased endothe-lial markers (VE-cadherin and CD31). In TGF61 stimulated HUVECs, we also observed that ONX0914 could inhibit endothelial-mesenchymal transition (EndMT). Mechanistically, we prove that ONX0914 could regulate autophagy activity both in vivo and vitro. Meanwhile, the protective effect of ONX0914 on TGF61 stimulated HUVECs could be abolished by 3-methyladenine (3MA) or hydroxychloroquine (CQ). All in all, our data highlight that inhi-bition of LMP7 with ONX0914 could ameliorate EndMT in diabetic mouse hearts at least in part via autophagy activation. Thus, LMP7 may be a potential therapeutic target for the DCM.
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关键词
immunoproteasome subunit lmp7,cardiomyopathy,endothelial-mesenchymal
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