N-glycosylation-mediated CD147 accumulation induces cardiac fibrosis in the diabetic heart through ALK5 activation

Abstract

Emerging evidence has implicated the important role of fibrosis in diabetic cardiomyopathy (DCM), while the underlying mechanism remains unclear. Considering the distinct and overlapping roles of Cluster of Differentiation 147 (CD147) in the pathogenesis of fibrotic diseases, we aim to investigate the role of CD147 in the fibrosis of DCM and explore its underlying mechanism. AAV9-mediated cardiac-specific CD147 silencing attenuated cardiac fibrosis and cardiac function in diabetic mice. CD147 knockdown significantly inhibited high glucose (HG)-induced activation of CFs. Mechanistically, CD147 directly bound to type I transcription growth factor β (TGF-β) receptor I (ALK5), promoting ALK5 activation and endocytosis to induce SMAD2/3 phosphorylation and nuclear translocation. In addition, HG prevented the ubiquitin-proteasome-dependent degradation of CD147 by promoting GNT-V-mediated N-glycosylation. As a result, cardiac-specific CD147 overexpression in control mice mimicked diabetes-induced cardiac fibrosis, aggravating cardiac function. Importantly, CD147 was also upregulated in serum and myocardial specimens from patients with diabetes compared with non-diabetes, accompanied by echocardiographic indices of cardiac dysfunction and excessive collagen deposition. Our study provides the first evidence that CD147 acts as a pivotal factor to promote diabetic cardiac fibrosis, and may contribute to the development of future CD147-based therapeutic strategies for DCM.

CD147 induces asthmatic airway remodeling and activation of circulating fibrocytes in a mouse model of asthma

“…As an extracellular matrix metalloproteinase inducer, CD147 has been reported to participate in tissue remodeling by regulating ECM deposition and degradation, cell adhesion, cell-cell interactions, and inducing myofibroblast differentiation [ 8 ]. Moreover, CD147 can modulate pulmonary fibrosis [ 22 ], liver fibrosis [ 23 ], cardiac fibrosis [ 24 ], along with regulation of MMPs, TGF-β1, α-SMA, or VEGF expression. Thus, whether and how anti-CD147 affect airway remodeling were investigated, and the result revealed that anti-CD147 treatment reduced airway goblet cell metaplasia, collagen deposition, and vascular remodeling in OVA-induced asthmatic mice, accompanied by inhibition of VEGF and α-SMA expression.…”

Pharmacological mechanisms of Taohe Chengqi decoction in diabetic cardiovascular complications: A systematic review, network pharmacology and molecular docking

“…And Li [ 21 ] observed by electron microscopy that THCQD could improve the ultrastructure of myogenic fibers and mitochondria in diabetic rat cardiac myocytes. Heart Injuries in DCM is associated with myocardial fibrosis, which is characterized by ventricular remodeling and interstitial fibrosis, ultimately leading to heart failure [ 37 ]. High blood glucose levels can alter cardiac metabolism and function, leading to cardiac stiffness, as well as systolic and relaxation dysfunction [ 38 ].…”