Key result
LUZP1 overexpression attenuates pressure overload-induced cardiac hypertrophy and dysfunction via Stat3 inhibition.
Why the study?
Cardiac hypertrophy contributes to heart failure with unclear mechanisms, and the role of leucine zipper protein 1 (LUZP1) in cardiac hypertrophy remains elusive.
LUZP1 represents a novel therapeutic target that attenuates pathological cardiac hypertrophy by upregulating SHP1 to inactivate Stat3 signaling.
LUZP1-Stat3 modulation merits further preclinical testing; leaves open any role in human heart failure therapy.
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.
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Fan et al. (2023) studied Cardiac hypertrophy. LUZP1 overexpression or deletion vs. Sham operation or matched control (wild-type/NTG/Flox) mice was evaluated on Cardiac hypertrophy and cardiac dysfunction. Cardiac-specific LUZP1 overexpression attenuated, while deficiency aggravated, pressure overload-induced cardiac hypertrophy and dysfunction in mice by inhibiting Stat3 signaling.
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