Journal of molecular and cellular cardiology · 2026
The mechanistic of DCBLD2 in inhibiting TGF-β induced endothelial-mesenchymal transition in calcific aortic valve disease.
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Yang Weiwei, Feng Qi, Yu Chao, Li Lijing, Zhang Siran, Nie Qihao, Wang Runtao, Zong Yanhong, Guo Lingling, Liu Xiaoning, Li Chenyang, Zhang Wenjun, Pei Yunli, Wang Huifang, Liu Demin, Niu Honglin, Nie Lei
Аннотация
OBJECTIVE: Despite significant elevations in the morbidity and mortality of calcific aortic valve disease (CAVD), no effective pharmacological treatments are currently available. This study aimed to elucidate the regulatory mechanisms of DCBLD2 in the pathogenesis of CAVD and to evaluate its potential as a novel therapeutic target for the treatment of CAVD.
METHODS: The assessment of DCBLD2 and Osteopontin levels was conducted through the utilisation of immunofluorescence and Western blot methodologies. Echocardiography was utilised to evaluate the aortic ejection function in murine subjects, while Von Kossa staining was employed to ascertain the extent of aortic valve calcification. The presence of endothelial and mesenchyme markers was determined through the implementation of Western blot and immunofluorescence techniques. The scratch test was performed in order to assess cell migration capacity. The levels of phosphorylation of proteins that are pivotal to the TGF-β signaling pathway were measured using Western blot analysis. The impact of DCBLD2 on TGF-β receptor (TGF-βR) and clathrin interactions was elucidated by conducting immunoprecipitation. To block clathrin activity, we selected Pitstop 2 as an inhibitor.
RESULTS: The expression levels of DCBLD2 were reduced in aortic valve tissue CAVD patients, and DCBLD2 knockout mice exhibited a significantly higher prevalence of CAVD compared to wild-type mice. Loss of DCBLD2 expression resulted in endothelial-to-mesenchymal transition (EndMT) in endothelial cells. A knockdown of DCBLD2 expression enhanced TGF-β signaling by upregulating clathrin-mediated endocytosis of TGF-βR.
CONCLUSION: Reduced DCBLD2 expression facilitates clathrin-mediated endocytosis of TGF-βR, leading to upregulated TGF-β signaling and EndMT induction in endothelial cells. These findings highlight DCBLD2 as a novel and critical target for pharmacological intervention in CAVD.
METHODS: The assessment of DCBLD2 and Osteopontin levels was conducted through the utilisation of immunofluorescence and Western blot methodologies. Echocardiography was utilised to evaluate the aortic ejection function in murine subjects, while Von Kossa staining was employed to ascertain the extent of aortic valve calcification. The presence of endothelial and mesenchyme markers was determined through the implementation of Western blot and immunofluorescence techniques. The scratch test was performed in order to assess cell migration capacity. The levels of phosphorylation of proteins that are pivotal to the TGF-β signaling pathway were measured using Western blot analysis. The impact of DCBLD2 on TGF-β receptor (TGF-βR) and clathrin interactions was elucidated by conducting immunoprecipitation. To block clathrin activity, we selected Pitstop 2 as an inhibitor.
RESULTS: The expression levels of DCBLD2 were reduced in aortic valve tissue CAVD patients, and DCBLD2 knockout mice exhibited a significantly higher prevalence of CAVD compared to wild-type mice. Loss of DCBLD2 expression resulted in endothelial-to-mesenchymal transition (EndMT) in endothelial cells. A knockdown of DCBLD2 expression enhanced TGF-β signaling by upregulating clathrin-mediated endocytosis of TGF-βR.
CONCLUSION: Reduced DCBLD2 expression facilitates clathrin-mediated endocytosis of TGF-βR, leading to upregulated TGF-β signaling and EndMT induction in endothelial cells. These findings highlight DCBLD2 as a novel and critical target for pharmacological intervention in CAVD.