Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death.However,the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear.Here,we identified that the expressio...Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death.However,the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear.Here,we identified that the expression of sterile alpha and TIR motif containing 1(SARM1),was increased significantly in the ischemic cardiomyopathy patients,dilated cardiomyopathy patients(GSE116250)and fibrotic heart tissues of mice.Additionally,inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction(MI)mice.Moreover,SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function.Mechanically,elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1.Notably,by using the Click-iT reaction,we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1,thereby accelerating the fibrosis process.Based on the fibrosis-promoting effect of SARM1,we screened several drugs with anti-myocardial fibrosis activity.In conclusion,we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis.Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis.The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.展开更多
The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia ...The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.展开更多
基金supported by grants from the National Natural Science Foundation of China(82370417,82270273,82330011,and U21A20339)Heilongjiang Province National Science Fund for Distinguished Young Scholars(JQ2024H001,China)CAMS Innovation Fund for Medical Sciences(2020-I2M-5-003,China)。
文摘Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death.However,the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear.Here,we identified that the expression of sterile alpha and TIR motif containing 1(SARM1),was increased significantly in the ischemic cardiomyopathy patients,dilated cardiomyopathy patients(GSE116250)and fibrotic heart tissues of mice.Additionally,inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction(MI)mice.Moreover,SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function.Mechanically,elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1.Notably,by using the Click-iT reaction,we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1,thereby accelerating the fibrosis process.Based on the fibrosis-promoting effect of SARM1,we screened several drugs with anti-myocardial fibrosis activity.In conclusion,we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis.Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis.The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.
基金the Arizona Biomedical Research Commission(ABRC)young investigator awardthe Fred Hutchinson Cancer Research Center(0000917241)Tulane University Startup fund。
文摘The critical roles of oxygen homeostasis in metabolism are indisputable and hypoxic responses are correlated with the pathogenesis of gastrointestinal, pulmonary, renal diseases and cancers. Evaluating tissue hypoxia to predict treatment outcome is challenging, however, due to the lack of rapid, accurate and non-invasive methods. Hypoxia enhances prolyl-4-hydroxylase a1(P4HA1) expression, which can convert bradykinin(BK) to hydroxyprolyl-BK(Hyp-BK), leading us to hypothesize that circulating Hyp-BK/BK ratios may reflect tissue hypoxia and predict treatment outcomes. Direct quantification of Hyp-BK peptides in serum or plasma by conventional MALDI-TOF MS analysis is technically challenging. In our study, a nanopore-based fractionation and enrichment protocol was utilized to allow the simple workflow for circulating Hyp-BK/BK analysis. Hypoxia is linked to poor prognosis due to its role in promoting pancreatic cancer progression and metastasis. Here we show that P4HA1 expression was increased in pancreatic tumors versus adjacent tissue, associated with poor survival, and corresponded with tumor expression of the hypoxia inducible factor 1a(HIF-1a) and carbonic anhydrase 9(CA9). Hypoxiainduced P4HA1 expression and BK conversion to Hyp-BK were found to be HIF-1 a dependent, pretreatment serum Hyp-BK/BK ratios corresponded with tissue HIF-1 a and P4HA1 expression, and high Hyp-BK/BK levels corresponded with poor response to therapy. These results suggest that pretreatment circulating Hyp-BK/BK ratios may have value as a non-invasive, surrogate indicator of tissue hypoxia and tumor responses to therapy.
