Leucine zipper protein 1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling
Di Fan1, Wan-Li Jiang2, Zhi-Li Jin1
1Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430062, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430062, China.
Insights
Leucine zipper protein 1 (LUZP1) inhibits cardiac hypertrophy by suppressing the Stat3 pathway. Targeting LUZP1 offers a potential therapeutic strategy for heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pathology
Background:
- Cardiac hypertrophy is a major cause of heart failure, with underlying mechanisms not fully understood.
- Leucine zipper protein 1 (LUZP1) is crucial for cardiovascular development, but its role in cardiac hypertrophy remains unclear.
Purpose of the Study:
- To investigate the molecular mechanisms of LUZP1 in cardiac hypertrophy.
- To explore LUZP1 as a potential therapeutic target for pathological cardiac hypertrophy.
Main Methods:
- Generated cardiac-specific LUZP1 knockout and transgenic mouse models.
- Utilized transverse aortic constriction (TAC) to induce pressure overload-induced cardiac hypertrophy.
- Performed transcriptome analysis and in vitro studies using neonatal rat cardiomyocytes.
Main Results:
- LUZP1 expression increased in hypertrophic hearts post-TAC.
- LUZP1 deficiency exacerbated cardiac hypertrophy, while LUZP1 overexpression attenuated it.
- LUZP1 inhibits cardiac hypertrophy by upregulating SHP1 to inactivate the Stat3 pathway.
Conclusions:
- LUZP1 attenuates pressure overload-induced cardiac hypertrophy by inhibiting Stat3 signaling.
- Targeting LUZP1 presents a novel therapeutic avenue for treating pathological cardiac hypertrophy.
Introduction:
Cardiac hypertrophy is an important contributor of heart failure, and the mechanisms remain unclear. Leucine zipper protein 1 (LUZP1) is essential for the development and function of cardiovascular system; however, its role in cardiac hypertrophy is elusive.
Objectives:
This study aims to investigate the molecular basis of LUZP1 in cardiac hypertrophy and to provide a rational therapeutic approach.
Methods:
Cardiac-specific Luzp1 knockout (cKO) and transgenic mice were established, and transverse aortic constriction (TAC) was used to induce pressure overload-induced cardiac hypertrophy. The possible molecular basis of LUZP1 in regulating cardiac hypertrophy was determined by transcriptome analysis. Neonatal rat cardiomyocytes were cultured to elucidate the role and mechanism of LUZP1 in vitro.
Results:
LUZP1 expression was progressively increased in hypertrophic hearts after TAC surgery. Gain- and loss-of-function methods revealed that cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated pressure overload-elicited hypertrophic growth and cardiac dysfunction in vivo and in vitro. Mechanistically, the transcriptome data identified Stat3 pathway as a key downstream target of LUZP1 in regulating pathological cardiac hypertrophy. Cardiac-specific Stat3 deletion abolished the pro-hypertrophic role in LUZP1 cKO mice after TAC surgery. Further findings suggested that LUZP1 elevated the expression of Src homology region 2 domain-containing phosphatase 1 (SHP1) to inactivate Stat3 pathway, and SHP1 silence blocked the anti-hypertrophic effects of LUZP1 in vivo and in vitro.
Conclusion:
We demonstrate that LUZP1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling, and targeting LUZP1 may develop novel approaches to treat pathological cardiac hypertrophy.
Related Concept Videos
01:20The JAK-STAT Signaling Pathway
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:29Heart Failure II: Pathophysiology
01:22Amplifying Signals via Enzymatic Cascade
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System