FOSL2 Regulates PANoptosis in Cardiomyocytes and Heart Failure Progression After Acute Myocardial Infarction by...

Area of Science:

• Cardiovascular Biology
• Cell Death Mechanisms
• Molecular Cardiology

Background:

• Postinfarction heart failure (HF) is a major clinical challenge.
• PANoptosis, a novel inflammatory cell death pathway, is implicated in various diseases.
• The role of NLRP12 in regulating PANoptosis during HF remains unclear.

Purpose of the Study:

• To investigate the role of NLRP12 in PANoptosis during postinfarction HF.
• To elucidate the regulatory mechanism of NLRP12 by FOSL2 in cardiomyocytes.
• To evaluate the therapeutic potential of targeting the FOSL2-NLRP12 axis in HF.

Main Methods:

• Acute myocardial infarction (AMI) model in C57BL/6J mice.
• Adeno-associated virus-mediated short hairpin RNA (AAV-shRNA) delivery to knockdown NLRP12.
• Lentiviral transduction of mouse cardiomyocytes under hypoxia.
• Western blotting and quantitative real-time PCR to assess protein and gene expression.
• Histological analysis for fibrosis and injury assessment.
• Echocardiography for cardiac function evaluation.

Main Results:

• NLRP12 and FOSL2 were significantly upregulated in myocardial tissues post-AMI and in hypoxia-exposed cardiomyocytes.
• FOSL2 directly activated NLRP12 transcription by binding to its promoter.
• Knockdown of FOSL2 or NLRP12 significantly improved cardiac function, reduced myocardial fibrosis and injury, and inhibited PANoptosis in mice with AMI.
• Combined overexpression of NLRP12 counteracted the protective effects of FOSL2 knockdown.

Conclusions:

• FOSL2 promotes cardiomyocyte PANoptosis by inducing NLRP12 transcription.
• The FOSL2-NLRP12 axis is a key driver of HF post-AMI.
• Targeting FOSL2 or NLRP12 represents a promising therapeutic strategy for postinfarction HF.