Loss of lims1 causes aberrant cardiac remodeling and heart failure via activating gp130/Jak1/Stat3 pathway in
Wuming Qin1, Xiaobo Yang1, Lu Zhang2
1Laboratory of Zebrafish Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.
Abstract:
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-of-function 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.
Insights
LIM zinc finger domain containing 1 (LIMS1) protein is crucial for heart integrity. Its deficiency causes heart failure by activating the gp130/Jak1/Stat3 pathway, offering new therapeutic targets for cardiac remodeling.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Genetics and Genomics
Background:
- LIM zinc finger domain containing 1 (LIMS1) is an adaptor protein involved in various diseases, but its role in cardiac pathologies is unknown.
- Understanding LIMS1's function is vital for exploring new therapeutic avenues in heart failure.
Purpose of the Study:
- To investigate the role and underlying mechanisms of LIMS1 in cardiac remodeling and heart failure.
- To determine if LIMS1 dysregulation contributes to dilated cardiomyopathy (DCM).
Main Methods:
- Elevated LIMS1 expression was identified in DCM patients and murine cardiomyocytes.
- A zebrafish model of lims1 loss-of-function mutant was generated using CRISPR/Cas9.
- Transcriptomic profiling and pharmacological inhibition of key signaling pathways were employed.
Main Results:
- LIMS1 deficiency in zebrafish led to severe cardiac remodeling, systolic dysfunction, and mortality.
- Transcriptomic analysis revealed hyperactivation of the gp130/Jak1/Stat3 signaling pathway in lims1-deficient hearts.
- Inhibition of Stat3 or c-Fos partially rescued cardiomyopathy phenotypes.
Conclusions:
- LIMS1 is essential for maintaining cardiac integrity.
- LIMS1 deficiency causes heart failure through hyperactivation of the gp130/Jak1/Stat3 pathway.
- Targeting Stat3 offers potential therapeutic strategies for LIMS1-related cardiac dysfunction.
