Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack...Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack of suitable,robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposi-tion.Here,we aim to establish a mouse model to mimic the development and features of CAVS.Methods:The model was established via aortic valve wire injury(AVWI)combined with vitamin D subcutaneous injected in wild type C57/BL6 mice.Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradi-ent.Histopathological specimens were collected and examined in respect of valve thickening,calcium deposition,collagen accumulation,osteogenic differentiation and inflammation.Results:Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time depend-ent manner and tended to be stable at 28 days.Compared with the sham group,sim-ple AVWI or the vitamin D group,the hybrid model group showed typical pathological features of CAVS,including hemodynamic alterations,increased aortic valve thicken-ing,calcium deposition,collagen accumulation at 28 days.In addition,osteogenic dif-ferentiation,fibrosis and inflammation,which play critical roles in the development of CAVS,were observed in the hybrid model.Conclusions:We established a novel mouse model of CAVS that could be induced efficiently,robustly and economically,and without genetic intervention.It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effec-tive pharmacological targets.展开更多
Atherosclerosis is featured as chronic low-grade inflammation in the arteries,which leads to the formation of plaques rich in lipids.M_(2)macrophage-derived extracellular vesicles(M_(2)EV)have significant potential fo...Atherosclerosis is featured as chronic low-grade inflammation in the arteries,which leads to the formation of plaques rich in lipids.M_(2)macrophage-derived extracellular vesicles(M_(2)EV)have significant potential for anti-atherosclerotic therapy.However,their therapeutic effectiveness has been hindered by their limited targeting capability in vivo.The objective of this study was to create the P-M_(2)EV(platelet membrane-modified M_(2)EV)using the membrane fusion technique in order to imitate the interaction between platelets and macrophages.P-M_(2)EV exhibited excellent physicochemical properties,and microRNA(miRNA)-sequencing revealed that the extrusion process had no detrimental effects on miRNAs carried by the nanocarriers.Remarkably,miR-99a-5p was identified as the miRNA with the highest expression level,which targeted the mRNA of Homeobox A1(HOXA1)and effectively suppressed the formation of foam cells in vitro.In an atherosclerotic low-density lipoprotein receptor-deficient(Ldlr^(-/-))mouse model,the intravenous injection of P-M_(2)EV showed enhanced targeting and greater infiltration into atherosclerotic plaques compared to regular extracellular vesicles.Crucially,P-M_(2)EV successfully suppressed the progression of atherosclerosis without causing systemic toxicity.The findings demonstrated a biomimetic platelet-mimic system that holds great promise for the treatment of atherosclerosis in clinical settings.展开更多
基金National Natural Science Foundation of China,Grant/Award Number:81770252,82030014,82271606 and U22A20267Binjiang Institute of Zhejiang University,Grant/Award Number:ZY202205SMKY001Key Program of Major Science and Technology Projects in Zhejiang Province,Grant/Award Number:2021C03097 and 2022C03063。
文摘Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack of suitable,robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposi-tion.Here,we aim to establish a mouse model to mimic the development and features of CAVS.Methods:The model was established via aortic valve wire injury(AVWI)combined with vitamin D subcutaneous injected in wild type C57/BL6 mice.Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradi-ent.Histopathological specimens were collected and examined in respect of valve thickening,calcium deposition,collagen accumulation,osteogenic differentiation and inflammation.Results:Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time depend-ent manner and tended to be stable at 28 days.Compared with the sham group,sim-ple AVWI or the vitamin D group,the hybrid model group showed typical pathological features of CAVS,including hemodynamic alterations,increased aortic valve thicken-ing,calcium deposition,collagen accumulation at 28 days.In addition,osteogenic dif-ferentiation,fibrosis and inflammation,which play critical roles in the development of CAVS,were observed in the hybrid model.Conclusions:We established a novel mouse model of CAVS that could be induced efficiently,robustly and economically,and without genetic intervention.It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effec-tive pharmacological targets.
基金supported by the National Natural Science Foundation of China(Grant 82070251 to M.X.).
文摘Atherosclerosis is featured as chronic low-grade inflammation in the arteries,which leads to the formation of plaques rich in lipids.M_(2)macrophage-derived extracellular vesicles(M_(2)EV)have significant potential for anti-atherosclerotic therapy.However,their therapeutic effectiveness has been hindered by their limited targeting capability in vivo.The objective of this study was to create the P-M_(2)EV(platelet membrane-modified M_(2)EV)using the membrane fusion technique in order to imitate the interaction between platelets and macrophages.P-M_(2)EV exhibited excellent physicochemical properties,and microRNA(miRNA)-sequencing revealed that the extrusion process had no detrimental effects on miRNAs carried by the nanocarriers.Remarkably,miR-99a-5p was identified as the miRNA with the highest expression level,which targeted the mRNA of Homeobox A1(HOXA1)and effectively suppressed the formation of foam cells in vitro.In an atherosclerotic low-density lipoprotein receptor-deficient(Ldlr^(-/-))mouse model,the intravenous injection of P-M_(2)EV showed enhanced targeting and greater infiltration into atherosclerotic plaques compared to regular extracellular vesicles.Crucially,P-M_(2)EV successfully suppressed the progression of atherosclerosis without causing systemic toxicity.The findings demonstrated a biomimetic platelet-mimic system that holds great promise for the treatment of atherosclerosis in clinical settings.
