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Fas Apoptosis Inhibitory Molecule 2 Inhibits Pathological Cardiac Hypertrophy by Regulating the MAPK Signaling
Huaping Zhong1,2, Minyu Wu3, Heping Xie2
1Suzhou Medical College of Soochow University Suzhou China.
Background:
Pathological cardiac hypertrophy stands as a pivotal mechanism contributing to diverse cardiovascular diseases, ultimately leading to heart failure. Despite its clinical significance, the intricate molecular mechanisms instigating pathological cardiac hypertrophy remain inadequately understood. In this study, we aim to further reveal its complex pathogenesis by exploring the role of Fas apoptotic inhibitory molecule 2 (FAIM2) in modulating pathological cardiac hypertrophy.
Methods And Results:
We used phenylephrine-induced hypertrophic cardiomyocytes and also generated cardiac-specific knockout mice and adeno-associated virus serotype 9-Faim2 mice to evaluate the function of FAIM2 in pathological myocardial hypertrophy. Furthermore, unbiased RNA-sequencing analysis was used to identify the direct target and corresponding molecular events contributing to FAIM2 function. Ultimately, our study revealed a downregulation of FAIM2 expression in phenylephrine-induced hypertrophic cardiomyocytes and pressure overload-induced hypertrophic hearts. FAIM2 exhibited a significant attenuation of phenylephrine-induced enlargement of primary neonatal rat cardiomyocytes, whereas FAIM2 knockdown aggravated the hypertrophic response. Furthermore, Faim2 gene knockout significantly exacerbated cardiac hypertrophy and heart fibrosis in vivo. Mechanistic investigations unveiled that FAIM2 exerts its inhibitory effect by suppressing TAK1-JNK1/2-p38 MAPK signaling cascades, thereby mitigating cardiac hypertrophy.
Conclusions:
Our findings position FAIM2 as a novel negative regulator of pathological cardiac hypertrophy through its inhibitory action on mitogen-activated protein kinase signaling activation. This identification of FAIM2's role provides crucial insights that may pave the way for the development of effective therapeutic strategies aimed at mitigating pathological cardiac hypertrophy, addressing a critical need in cardiovascular disease management.
Insights
Fas apoptotic inhibitory molecule 2 (FAIM2) is a novel negative regulator of pathological cardiac hypertrophy. Downregulation of FAIM2 exacerbates cardiac hypertrophy and fibrosis by activating MAPK signaling pathways.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Signaling
Background:
- Pathological cardiac hypertrophy is a key driver of cardiovascular diseases and heart failure.
- The molecular mechanisms underlying cardiac hypertrophy are not fully understood.
- Fas apoptotic inhibitory molecule 2 (FAIM2) is investigated for its role in cardiac hypertrophy.
Purpose of the Study:
- To elucidate the role of FAIM2 in the pathogenesis of pathological cardiac hypertrophy.
- To identify the molecular targets and pathways regulated by FAIM2 in cardiac hypertrophy.
Main Methods:
- Utilized phenylephrine-induced hypertrophic cardiomyocytes.
- Generated cardiac-specific Faim2 knockout and AAV-Faim2 overexpression mouse models.
- Performed unbiased RNA-sequencing analysis.
- Investigated signaling pathways including TAK1-JNK1/2-p38 MAPK.
Main Results:
- FAIM2 expression was downregulated in hypertrophic cardiomyocytes and hearts.
- FAIM2 overexpression attenuated, while FAIM2 knockdown aggravated, cardiomyocyte hypertrophy.
- Faim2 gene knockout exacerbated cardiac hypertrophy and fibrosis in vivo.
- FAIM2 suppressed TAK1-JNK1/2-p38 MAPK signaling.
Conclusions:
- FAIM2 acts as a novel negative regulator of pathological cardiac hypertrophy.
- FAIM2 mitigates cardiac hypertrophy by inhibiting MAPK signaling activation.
- FAIM2 represents a potential therapeutic target for cardiovascular disease management.
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