FOSL2 drives cardiomyocyte PANoptosis and heart failure progression post-AMI by activating NLRP12 transcription
Background
The progression of heart failure (HF) following acute myocardial infarction (AMI) is critically influenced by regulated cell death. Unlike apoptosis, PANoptosis represents a highly inflammatory form of lytic cell death, combining features of pyroptosis, necroptosis, and apoptosis, which can exacerbate tissue damage and inflammation. Understanding the specific molecular regulators of PANoptosis in cardiomyocytes post-AMI is crucial for developing targeted therapies. This study investigates the role of NLRP12, a known inducer of PANoptosis, and its upstream regulator FOSL2 in the context of post-infarction heart failure.
Study Design
Researchers investigated NLRP12's role in post-infarction heart failure using C57BL/6J mice. Mice received AAV-shNLRP12 before AMI modeling via coronary artery ligation. Separately, mouse cardiomyocytes were treated with lentiviruses (for knockdown or overexpression) before hypoxia exposure. The study assessed survival, cardiac function, myocardial fibrotic area, myocardial injury markers, and the extent of PANoptosis. The primary endpoint was the impact of FOSL2 and NLRP12 modulation on heart failure progression and cardiomyocyte death.
Results
Both NLRP12 and FOSL2 were significantly upregulated in myocardial tissues of AMI-induced mice and in hypoxia-exposed mouse cardiomyocytes. Mechanistically, FOSL2 was found to activate NLRP12 in mouse cardiomyocytes by directly binding to its promoter, thereby promoting its transcription. The most significant finding demonstrated that:
Knockdown of either
FOSL2orNLRP12improved survival and inhibited heart failure progression afterAMIin mice. This included a recovery of cardiac function, a reduction of fibrotic area in myocardial tissues, a decrease in myocardial injury, and a clear inhibition of PANoptosis in cardiomyocytes. Conversely, combined overexpression ofNLRP12impaired the beneficial inhibitory effect ofFOSL2knockdown on heart failure afterAMI, confirmingNLRP12as a downstream effector.
Key Findings
FOSL2andNLRP12were upregulated in myocardial tissues post-AMIand in hypoxic cardiomyocytes.FOSL2activatedNLRP12transcription in cardiomyocytes by binding to its promoter.- Knockdown of
FOSL2orNLRP12improved survival and inhibited heart failure afterAMI. - Knockdown of
FOSL2orNLRP12led to recovery of cardiac function and reduced myocardial fibrosis. - Combined
NLRP12overexpression impaired the protective effects ofFOSL2knockdown post-AMI.
Why It Matters
This research identifies FOSL2 and NLRP12 as critical drivers of PANoptosis and heart failure progression post-AMI, offering novel therapeutic targets. Targeting the FOSL2-NLRP12 axis could provide a new strategy to mitigate myocardial damage and improve outcomes in patients after a heart attack. While currently preclinical, these findings lay the groundwork for developing gene therapies or small molecule inhibitors that could prevent the detrimental inflammatory cell death cascade. Future research will need to translate these findings into human-relevant models and assess the safety and efficacy of FOSL2 or NLRP12 modulation in a clinical setting, potentially altering post-AMI care protocols.
heart-failure
myocardial-infarction
panoptosis
nlrp12
fosl2
inflammation