The Role of CD147 in Pathological Cardiac Hypertrophy Is Regulated by Glycosylation

Abstract

CD147, also known as EMMPRIN or basigin, is a transmembrane glycoprotein receptor that activates matrix metalloproteinases and promotes inflammation. CD147 function is regulated by posttranslational modifications of which glycosylation has attracted the most attention. In this study, we demonstrated that glycosylated CD147 was the dominant form in heart tissue, and its levels were markedly elevated in response to transverse aortic constriction (TAC). Adeno-associated virus 9-mediated, cardiac-specific overexpression of wild-type CD147 in mice significantly promoted pressure overload-induced pathological cardiac remodeling accompanied by augmented oxidative stress and ferroptosis. By contrast, mutations of CD147 glycosylation sites notably weakened these detrimental effects of CD147. Mechanistically, CD147 exacerbated TAC-induced pathological cardiac remodeling via direct binding with the adaptor molecule TRAF2 and subsequent activation of TAK1 signalling, which was dependent on glycosylation of CD147. Collectively, our findings provide the first evidence that CD147 promoted pathological cardiac remodeling and dysfunction in a glycosylation-dependent manner through binding the adaptor protein TRAF2 and activating the downstream TRAF2-TAK1 signalling pathway. Thus, glycosylation of CD147 may be a potent interventional target for heart failure treatment.

Defining cardiac fibrosis complexity and regulation towards therapeutic development

“…189 Indeed, p38 kinase signalling and cardiac fibrosis can be inhibited by matrine, 190 a plant alkaloid with few adverse effects. Additionally, regulation of other post-translational modifications may offer therapeutic benefits; modulation of HSP90 S-nitrosylation 41 and CD147 glycosylation 191 significantly altered cardiac fibrosis levels in vivo. The development of innovative strategies to influence protein modifications may provide novel treatment options.…”

COVID-19 vaccine adverse events: Evaluating the pathophysiology from an undersulfated and degraded glycocalyx perspective

“…It participates in many physiological and pathological processes due to its numerous interacting partners 127 . CD147, a versatile transmembrane glycoprotein, promotes the activation of matrix metalloproteinase (MMP), myofibroblast differentiation, fibrosis, and oxidative stress 130 . CD147 is also highly expressed in immune cells, EnCs in the brain, tissues of the gastrointestinal tract, platelets, conjunctival tissues, kidney glomerular cells and podocytes, and cardiac pericytes.…”

“…Furthermore, CD147 plays pleiotropic molecular roles in various physiological conditions, such as spermatogenesis, fertilization, neural networks, and retinal development. It can result in pathological conditions, such as tumor progression, inflammatory response, plasmodium invasion, and rheumatoid arthritis, in addition to facilitating viral infection 126,130 . Endocytosis is a vital entry mode for viral infection, and Zhou et al demonstrated that SARS-CoV-2 enters host cells through CD147-mediated endocytosis 126 .…”

Emerging roles of ferroptosis in cardiovascular diseases

“…CD147 is a transmembrane glycoprotein receptor that activates matrix metalloproteinases and promotes inflammation [ 90 ]. Zhong et al demonstrated that CD147 promotes pathological cardiac remodelling and dysfunction in a glycation-dependent manner by binding to the adapter protein TRAF2 and activating the downstream TAK1 signalling pathway, which is accompanied by increased oxidative stress and ferroptosis [ 91 ].…”