MicroRNA-103/107 Regulate Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury Through Targeting FADD

Area of Science:

• Cardiovascular Biology
• Molecular Cell Biology
• RNA Biology

Background:

• Cardiomyocyte death, particularly necrosis, is a key feature of heart disease.
• Regulated forms of necrosis involve receptor-interacting serine/threonine-protein kinases (RIPK1 and RIPK3) and may be modulated by Fas-associated protein with death domain (FADD).
• MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in cellular processes.

Purpose of the Study:

• To investigate the roles of microRNA-103/107 and H19 in regulating RIPK1- and RIPK3-dependent necrosis.
• To determine if these molecules target FADD in cardiomyocyte-derived H9c2 cells and in a myocardial infarction model.
• To elucidate a novel regulatory pathway for myocardial necrosis.

Main Methods:

• Utilized H9c2 cells and a mouse ischemia/reperfusion model to study necrosis.
• Investigated the interaction between FADD, RIPK1, and RIPK3 complexes in H2O2-induced necrosis.
• Employed techniques to assess miRNA and lncRNA targeting and regulation of FADD expression.
• Examined the effect of modulating miR-103/107 levels on necrosis.

Main Results:

• FADD plays a role in H2O2-induced necrosis by affecting RIPK1 and RIPK3 complex formation in H9c2 cells.
• MicroRNA-103/107 directly target FADD, and their knockdown reduces necrosis in cellular and in vivo models.
• The miR-103/107-FADD pathway is not involved in tumor necrosis factor-α-induced necrosis.
• Long noncoding RNA H19 directly binds to miR-103/107, regulating FADD expression and necrosis.

Conclusions:

• A novel regulatory model for myocardial necrosis involving H19, miR-103/107, and FADD has been identified.
• This pathway is specific to certain types of necrosis, distinct from TNF-α-induced necrosis.
• Modulating the levels of H19, miR-103/107, and FADD presents a potential therapeutic strategy for preventing myocardial necrosis.