Previous studies suggested a beneficial effect of natriuretic peptides in animal models of cardiovascular disease,but the role of natriuretic peptide receptor C(NPRC)in the pathogenesis of atherosclerosis(AS)remains u...Previous studies suggested a beneficial effect of natriuretic peptides in animal models of cardiovascular disease,but the role of natriuretic peptide receptor C(NPRC)in the pathogenesis of atherosclerosis(AS)remains unknown.This study was designed to test the hypothesis that NPRC may promote AS lesion formation and instability by enhancing oxidative stress,inflammation,and apoptosis via protein kinase A(PKA)signaling.ApoE^(−/−)mice were fed chow or Western diet for 12 weeks and NPRC expression was significantly increased in the aortic tissues of Western diet-fed mice.Systemic NPRC knockout mice were crossed with ApoE^(−/−)mice to generate ApoE^(−/−)NPRC^(−/−)mice,and NPRC deletion resulted in a significant decrease in the size and instability of aortic atherosclerotic lesions in ApoE^(−/−)NPRC^(−/−)versus ApoE^(−/−)mice.In addition,endothelial cell-specific NPRC knockout attenuated atherosclerotic lesions in mice.In contrast,endothelial cell overexpression of NPRC aggravated the size and instability of atherosclerotic aortic lesions in mice.Experiments in vitro showed that NPRC knockdown in human aortic endothelial cells(HAECs)inhibited ROS production,pro-inflammatory cytokine expression and endothelial cell apoptosis,and increased eNOS expression.Furthermore,NPRC knockdown in HAECs suppressed macrophage migration,cytokine expression,and phagocytosis via its effects on endothelial cells.On the contrary,NPRC overexpression in endothelial cells resulted in opposite effects.Mechanistically,the anti-inflammation and anti-atherosclerosis effects of NPRC deletion involved activation of cAMP/PKA pathway,leading to downstream upregulated AKT1 pathway and downregulated NF-κB pathway.In conclusion,NPRC deletion reduced the size and instability of atherosclerotic lesions in ApoE^(−/−)mice via attenuating inflammation and endothelial cell apoptosis and increasing eNOS expression by modulating cAMP/PKA-AKT1 and NF-κB pathways.Thus,targeting NPRC may provide a promising approach to the prevention and treatment of atherosclerosis.展开更多
The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear.This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 m...The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear.This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicininduced cardiomyopathy.C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy.Cardiomyocyte-specific ADAM17-knockout(A17^(α-MHCKO))and ADAM17-overexpressing(AAV9-oeA17)mice were generated.In addition,RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes(NRCMs)receiving different treatment were performed.Mouse tumor models were constructed in A17^(fl/fl )and A17α-MHCKO mice.In addition,cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated.ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs.A17^(α-MHCKO) mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17^(fl/fl) mice,and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin.In contrast,AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment.Mechanistically,doxorubicin enhanced the expression of transcription factor C/EBPβ,leading to increased expression and activity of ADAM17 in cardiomyocyte,which enhanced TNF-αshedding and upregulated the expression of TRAF3.Increased TRAF3 promoted TAK1 autophosphorylation,resulting in activated MAPKs pathway and cardiomyocyte apoptosis.ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling.Thus,targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.展开更多
After online publication of the article,the authors noticed one inadvertent mistake in Fig.2b.The image of Sirus Red Dark in ApoE^(-/-)NPRC^(-/-)group Was mistakenly inserted as the image of Sirus Red Bright in ApoE^(...After online publication of the article,the authors noticed one inadvertent mistake in Fig.2b.The image of Sirus Red Dark in ApoE^(-/-)NPRC^(-/-)group Was mistakenly inserted as the image of Sirus Red Bright in ApoE^(-/-)group,during the final revision process.The correct figure was provided as follows.展开更多
基金This work was supported by grants of the National Natural Science Foundation of China(No.82241203,81920108003,82030051,81970366,82000411,82200498,and 82200502)State Key R&D Program of China(2021YFF0501403)+2 种基金Key R&D Program of Shandong Province(2021SFGC0503,2021ZLGX02,2021ZDSYS05,and 2020ZLYS05)Shandong Provincial Natural Science Foundation(ZR2020QH023,ZR2022QH026,and ZR2022QH089)the Taishan Scholars Program of Shandong Province(Zhang C,Zhang M).
文摘Previous studies suggested a beneficial effect of natriuretic peptides in animal models of cardiovascular disease,but the role of natriuretic peptide receptor C(NPRC)in the pathogenesis of atherosclerosis(AS)remains unknown.This study was designed to test the hypothesis that NPRC may promote AS lesion formation and instability by enhancing oxidative stress,inflammation,and apoptosis via protein kinase A(PKA)signaling.ApoE^(−/−)mice were fed chow or Western diet for 12 weeks and NPRC expression was significantly increased in the aortic tissues of Western diet-fed mice.Systemic NPRC knockout mice were crossed with ApoE^(−/−)mice to generate ApoE^(−/−)NPRC^(−/−)mice,and NPRC deletion resulted in a significant decrease in the size and instability of aortic atherosclerotic lesions in ApoE^(−/−)NPRC^(−/−)versus ApoE^(−/−)mice.In addition,endothelial cell-specific NPRC knockout attenuated atherosclerotic lesions in mice.In contrast,endothelial cell overexpression of NPRC aggravated the size and instability of atherosclerotic aortic lesions in mice.Experiments in vitro showed that NPRC knockdown in human aortic endothelial cells(HAECs)inhibited ROS production,pro-inflammatory cytokine expression and endothelial cell apoptosis,and increased eNOS expression.Furthermore,NPRC knockdown in HAECs suppressed macrophage migration,cytokine expression,and phagocytosis via its effects on endothelial cells.On the contrary,NPRC overexpression in endothelial cells resulted in opposite effects.Mechanistically,the anti-inflammation and anti-atherosclerosis effects of NPRC deletion involved activation of cAMP/PKA pathway,leading to downstream upregulated AKT1 pathway and downregulated NF-κB pathway.In conclusion,NPRC deletion reduced the size and instability of atherosclerotic lesions in ApoE^(−/−)mice via attenuating inflammation and endothelial cell apoptosis and increasing eNOS expression by modulating cAMP/PKA-AKT1 and NF-κB pathways.Thus,targeting NPRC may provide a promising approach to the prevention and treatment of atherosclerosis.
基金supported by grants of the National Natural Science Foundation of China(Nos.82000411,82030051,82241203,81920108003 and 81970366)State Key R&D Program of China(2021YFF0501403)+4 种基金Key R&D Program of Shandong Province(2021SFGC0503,2021ZLGX02,2021ZDSYS05,2020ZLYS05)Shandong Provincial Natural Science Foundation(ZR2020QH023)the Taishan Scholars Program of Shandong Province(C.Z.)China Postdoctoral Science Foundation(2023M742124)Postdoctoral Innovation Talents Support Program(BX20230210).
文摘The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear.This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition of ADAM17 may ameliorate doxorubicininduced cardiomyopathy.C57BL/6J mice were intraperitoneally injected with a cumulative dose of doxorubicin to induce cardiomyopathy.Cardiomyocyte-specific ADAM17-knockout(A17^(α-MHCKO))and ADAM17-overexpressing(AAV9-oeA17)mice were generated.In addition,RNA sequencing of the heart tissues in different mouse groups and in vitro experiments in neonatal rat cardiomyocytes(NRCMs)receiving different treatment were performed.Mouse tumor models were constructed in A17^(fl/fl )and A17α-MHCKO mice.In addition,cardiomyocyte-specific TRAF3-knockdown and TRAF3-overexpressing mice were generated.ADAM17 expression and activity were markedly upregulated in doxorubicin-treated mouse hearts and NRCMs.A17^(α-MHCKO) mice showed less cardiomyocyte apoptosis induced by doxorubicin than A17^(fl/fl) mice,and cardiomyocyte ADAM17 deficiency did not affect the anti-tumor effect of doxorubicin.In contrast,AAV9-oeA17 mice exhibited markedly aggravated cardiomyocyte apoptosis relative to AAV9-oeNC mice after doxorubicin treatment.Mechanistically,doxorubicin enhanced the expression of transcription factor C/EBPβ,leading to increased expression and activity of ADAM17 in cardiomyocyte,which enhanced TNF-αshedding and upregulated the expression of TRAF3.Increased TRAF3 promoted TAK1 autophosphorylation,resulting in activated MAPKs pathway and cardiomyocyte apoptosis.ADAM17 acted as a positive regulator of cardiomyocyte apoptosis and cardiac remodeling and dysfunction induced by doxorubicin by upregulating TRAF3/TAK1/MAPKs signaling.Thus,targeting ADAM17/TRAF3/TAK1/MAPKs signaling holds a promising potential for treating doxorubicin-induced cardiotoxicity.
文摘After online publication of the article,the authors noticed one inadvertent mistake in Fig.2b.The image of Sirus Red Dark in ApoE^(-/-)NPRC^(-/-)group Was mistakenly inserted as the image of Sirus Red Bright in ApoE^(-/-)group,during the final revision process.The correct figure was provided as follows.
