LIM zinc finger domain containing 1(LIMS1),an evolutionarily conserved LIM domain adaptor protein,is implicated in diverse pathologies,including cancer and neurological disorders.However,its roles in cardiac diseases ...LIM zinc finger domain containing 1(LIMS1),an evolutionarily conserved LIM domain adaptor protein,is implicated in diverse pathologies,including cancer and neurological disorders.However,its roles in cardiac diseases and the underlying mechanisms remain unclear.Here,we explore the functions and mechanisms of LIMS1 in cardiac remodeling and heart failure.We identify the elevated LIMS1 expression in patients with dilated cardiomyopathy and murine cardiomyocytes,suggesting that LIMS1 dysregulation contributes to cardiac pathology.Using CRISPR/Cas9 technology,we generate a zebrafish model of lims1 loss-offunction mutant,which exhibits severe cardiac chamber remodeling,systolic dysfunction,and premature mortality,demonstrating the essential role of lims1 in maintaining cardiac integrity.Transcriptomic profiling reveals the activation of the gp130/Jak1/Stat3 signaling in the lims1-deficient hearts.Strikingly,pharmacological inhibition of Stat3 or c-Fos partially rescues cardiomyopathy phenotypes.Our findings reveal the underlying mechanism of lims1 deficiency-caused heart failure through gp130/Jak1/Stat3 hyperactivation,offering insights into cardiac remodeling and potential therapeutic strategies.展开更多
基金the National Natural Science Foundation of China(82070394,82371863,31970504,82100491,and 82000307)the Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control project(HPKL2023001)for their support of this research.
文摘LIM zinc finger domain containing 1(LIMS1),an evolutionarily conserved LIM domain adaptor protein,is implicated in diverse pathologies,including cancer and neurological disorders.However,its roles in cardiac diseases and the underlying mechanisms remain unclear.Here,we explore the functions and mechanisms of LIMS1 in cardiac remodeling and heart failure.We identify the elevated LIMS1 expression in patients with dilated cardiomyopathy and murine cardiomyocytes,suggesting that LIMS1 dysregulation contributes to cardiac pathology.Using CRISPR/Cas9 technology,we generate a zebrafish model of lims1 loss-offunction mutant,which exhibits severe cardiac chamber remodeling,systolic dysfunction,and premature mortality,demonstrating the essential role of lims1 in maintaining cardiac integrity.Transcriptomic profiling reveals the activation of the gp130/Jak1/Stat3 signaling in the lims1-deficient hearts.Strikingly,pharmacological inhibition of Stat3 or c-Fos partially rescues cardiomyopathy phenotypes.Our findings reveal the underlying mechanism of lims1 deficiency-caused heart failure through gp130/Jak1/Stat3 hyperactivation,offering insights into cardiac remodeling and potential therapeutic strategies.
