CIRC-MARC2 SILENCING PROTECTS HUMAN CARDIOMYOCYTES FROM HYPOXIA/REOXYGENATION-INDUCED INJURY BY MODULATING...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Physiology

Background:

• Myocardial ischemia-reperfusion injury (MIRI) is a significant contributor to cardiovascular disease mortality.
• Circular RNAs (circRNAs) are emerging as key regulators in various biological processes, including MIRI.
• The specific role of circ-mitochondrial amidoxime reducing component 2 (circ-MARC2) in MIRI remains largely uncharacterized.

Purpose of the Study:

• To investigate the expression and function of circ-MARC2 in myocardial ischemia-reperfusion injury.
• To elucidate the molecular mechanism underlying circ-MARC2's involvement in hypoxia/reoxygenation (H/R)-induced cardiomyocyte damage.
• To explore the potential therapeutic implications of targeting the circ-MARC2/miR-335-5p/TRPM7 axis.

Main Methods:

• AC16 cells were subjected to hypoxia/reoxygenation (H/R) to mimic MIRI conditions.
• Circ-MARC2 expression levels were assessed using quantitative real-time PCR.
• Cell proliferation, lactate dehydrogenase (LDH) activity, creatine kinase (CK) activity, and apoptosis were measured.
• RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were performed to confirm the interaction between circ-MARC2, miR-335-5p, and TRPM7.

Main Results:

• Circ-MARC2 was significantly overexpressed in H/R-treated AC16 cells.
• Silencing circ-MARC2 attenuated H/R-induced cardiomyocyte injury, reducing LDH and CK activities and apoptosis while enhancing cell proliferation.
• Circ-MARC2 acted as a molecular sponge for miR-335-5p, inhibiting its activity.
• miR-335-5p directly targeted and downregulated the expression of transient receptor potential cation channel subfamily M member 7 (TRPM7).
• Overexpression of miR-335-5p protected against H/R-induced damage, an effect abolished by TRPM7 upregulation.
• Knockdown of circ-MARC2 alleviated H/R-induced injury by regulating the miR-335-5p/TRPM7 axis.

Conclusions:

• Circ-MARC2 plays a detrimental role in myocardial ischemia-reperfusion injury by sponging miR-335-5p and upregulating TRPM7.
• The circ-MARC2/miR-335-5p/TRPM7 pathway represents a potential therapeutic target for mitigating MIRI.
• Targeting circ-MARC2 may offer a novel strategy for treating cardiovascular diseases associated with MIRI.