Pulsatile flow increases METTL14-induced m 6 A modification and attenuates septic cardiomyopathy: an experimental...

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Sepsis Research

Background:

• Septic cardiomyopathy, a severe complication of sepsis, involves microcirculatory malperfusion.
• Pulsatile flow shows protective effects in microcirculatory disturbances, but mechanisms remain unclear.
• N6-methyladenosine (m6A) modification is implicated in various cellular processes.

Purpose of the Study:

• To investigate the role of m6A modification in septic cardiomyopathy.
• To elucidate the mechanisms by which extracorporeal membrane oxygenation (ECMO)-generated pulsatile flow alleviates septic cardiomyopathy.

Main Methods:

• Established a rat model of septic cardiomyopathy supported by ECMO with pulsatile or non-pulsatile flow.
• Assessed microcirculatory perfusion index (PPI) and cardiac function via ultrasonography.
• Quantified m6A levels and gene/protein expression using molecular biology techniques (dot blot, qRT-PCR, Western blot, immunofluorescence, immunohistochemistry, RNA immunoprecipitation).

Main Results:

• Pulsatile flow significantly improved PPI, cardiac function, endothelial protection, and survival in septic cardiomyopathy models.
• Pulsatile flow induced METTL14-mediated m6A modification of zonula occludens-1 (ZO-1) mRNA, stabilized by YTHDF2.
• Pulsatile flow suppressed the PI3K-Akt pathway, reducing Foxo1 inhibition of METTL14, thereby enhancing m6A modification.

Conclusions:

• ECMO-generated pulsatile flow enhances METTL14-mediated m6A modification of ZO-1 mRNA, attenuating septic cardiomyopathy progression.
• Pulsatility may represent a novel therapeutic strategy for septic cardiomyopathy by mitigating microcirculatory disturbances.