Negative feedback of SNRK to circ-SNRK regulates cardiac function post-myocardial infarction

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• RNA Biology

Background:

• Myocardial infarction (MI) impairs cardiac function, often leading to heart failure due to reduced oxygen and substrate delivery.
• Cardiac mitochondrial efficiency is crucial for maintaining heart function and energy metabolism.

Purpose of the Study:

• To identify novel regulatory mechanisms of cardiac energy metabolism in response to ischemia.
• To investigate the role of circular RNAs in the pathophysiology of heart failure post-MI.

Main Methods:

• Identification and characterization of circ-SNRK in cardiomyocytes (CMs).
• Investigation of the circ-SNRK interaction with miR-33 and SNRK (sucrose nonfermenting 1-related kinase).
• Analysis of NOVA1 (NOVA alternative splicing regulator 1) involvement in circ-SNRK formation.
• In vivo studies using rat models of myocardial infarction.

Main Results:

• Circ-SNRK sponges miR-33, enhancing ATP synthesis via SNRK, establishing a circ-SNRK-miR-33-SNRK axis.
• A negative feedback loop involving SNRK cleavage, nuclear entry, and NOVA1 binding inhibits circ-SNRK formation.
• Overexpression of exogenous circ-SNRK improved cardiac function in rats post-MI, breaking the inhibitory loop.

Conclusions:

• The circ-SNRK/SNRK negative feedback loop regulates cardiomyocyte (CM) energy metabolism.
• Circ-SNRK represents a potential therapeutic target for heart failure by modulating cardiac energy metabolism.