Response by Pan and Sun to Letter Regarding Article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture”

HomeCirculationVol. 146, No. 11Response by Pan and Sun to Letter Regarding Article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Pan and Sun to Letter Regarding Article, “Legumain Is an Endogenous Modulator of Integrin αvβ3 Triggering Vascular Degeneration, Dissection, and Rupture” Lihong Pan, PhD and Aijun Sun, PhD Lihong PanLihong Pan https://orcid.org/0000-0002-1995-2373 Institutes of Biomedical Science and Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. Search for more papers by this author and Aijun SunAijun Sun https://orcid.org/0000-0003-1488-0937 Institutes of Biomedical Science and Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. Search for more papers by this author Originally published12 Sep 2022https://doi.org/10.1161/CIRCULATIONAHA.122.060916Circulation. 2022;146:e144–e145In Response:We appreciate the comments by Wang et al on our recent publication.1 In our article, we reveal that Lgmn (legumain) exacerbates aortic dissection mainly by degrading the extracellular matrix and promoting the phenotype transformation of smooth muscle cells without affecting inflammatory response, which corresponds with a previous study that Lgmn promotes pulmonary hypertension by activating matrix metalloproteinase)-2/ transforming growth factor-β1 signaling without affecting inflammatory cell infiltration.2 Another study also shows that Lgmn knockout suppressed rUCCAO-induced microglial activation and reduced the abnormal expression of inflammatory cytokines and the inflammasome complex.3 Moreover, Lgmn is also known to enhance the inflammatory M1 phenotype and oxidized low-density lipoprotein–induced foam cell formation in macrophages.4 These studies reveal that Lgmn will promote the inflammatory response. In our study, we assessed inflammation at 28 days after modeling and found no difference between the wild-type and Lgmn knockout groups. However, it is unclear whether Lgmn will play a role in inflammatory response at 7, 14, or 21 days after modeling, which needs further study.Peripheral artery disease of the lower extremity is one of the common macrovascular complications of diabetes and occurs at the terminal stage of diabetes. A logistic regression study showed that a higher serum Lgmn level was independently associated with a greater risk of peripheral artery disease in patients with type 2 diabetes.5 Age is the major risk factor for Alzheimer disease. Study also shows that mature Lgmn (asparagine endopeptidase) is activated in aging brain; it is also activated in both human brains with Alzheimer disease and tau P301S transgenic mice. Asparagine endopeptidase gene deficiency prevents tau phosphorylation, synaptic dysfunction, and memory deficits in the tau P301S mouse. Asparagine endopeptidase acts as a crucial mediator of tau-related clinical and neuropathological changes. Inhibition of asparagine endopeptidase may be therapeutically useful for treating tau-mediated neurodegenerative diseases.6 Peripheral artery disease and Alzheimer disease are highly prevalent in the elderly. These findings demonstrate that Lgmn deficiency would have positive effects in some age-related diseases. Aortic dissection is also closely related to older age. In our research, we collected the tissue and serum of patients with aortic dissection and detected the Lgmn level. We found a positive correlation between Lgmn level and aortic dissection. RR-11a is an inhibitor of Lgmn and may be a promising clinical treatment agent. The effect of Lgmn deficiency in aortic dissection progression in elderly patients needs further study.Article InformationDisclosures None.FootnotesCirculation is available at www.ahajournals.org/journal/circReferences1. Pan L, Bai P, Weng X, Liu J, Chen Y, Chen S, Ma X, Hu K, Sun A, Ge J. Legumain is an endogenous modulator of integrin αvβ3 triggering vascular degeneration, dissection, and rupture.Circulation. 2022; 145:659–674. doi: 10.1161/CIRCULATIONAHA.121.056640LinkGoogle Scholar2. Bai P, Lyu L, Yu T, Zuo C, Fu J, He Y, Wan Q, Wan N, Jia D, Lyu A. Macrophage-derived legumain promotes pulmonary hypertension by activating the MMP (matrix metalloproteinase)-2/TGF (transforming growth factor)-beta1 signaling.Arterioscler Thromb Vasc Biol. 2019; 39:e130–e145. doi: 10.1161/ATVBAHA.118.312254LinkGoogle Scholar3. Chai X, Li X, Zhang W, Tan X, Wang H, Yang Z. Legumain knockout improved cognitive impairment via reducing neuroinflammation in right unilateral common carotid artery occlusion mice.Life Sci. 2021; 285:119944. doi: 10.1016/j.lfs.2021.119944CrossrefMedlineGoogle Scholar4. Ozawa N, Sato Y, Mori Y, Masuda H, Yamane M, Yamamoto Y, Shirai R, Watanabe R, Sato K, Mori Y, et al. Legumain promotes atherosclerotic vascular remodeling.Int J Mol Sci. 2019; 20:2195. doi: 10.3390/ijms20092195CrossrefGoogle Scholar5. Wei W, Chen S, Huang J, Tong Y, Zhang J, Qiu X, Zhang W, Chen H, Huang R, Cai J., et al. Serum legumain is associated with peripheral artery disease in patients with type 2 diabetes.J Diabetes Res. 2021; 2021:5651469. doi: 10.1155/2021/5651469CrossrefMedlineGoogle Scholar6. Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, Seyfried NT, Hu WT, Liu Z, Wang JZ, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease.Nat Med. 2014; 20:1254–1262. doi: 10.1038/nm.3700CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails September 13, 2022Vol 146, Issue 11 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.060916PMID: 36095064 Originally publishedSeptember 12, 2022 PDF download Advertisement SubjectsRehabilitationTransplantation