MiR-499-5P/PACS2/TRPV1 Axis Maintains Mitochondrial Homeostasis and Left Ventricular Function after Extreme Cold...

Area of Science:

• Cardiology
• Molecular Biology
• Environmental Physiology

Background:

• Extreme cold stress (ECS) poses significant physiological challenges, notably impairing left ventricular (LV) function.
• Understanding the molecular mechanisms underlying ECS-induced cardiac injury is crucial for developing preventative strategies.

Purpose of the Study:

• To investigate the role of the miR-499-5p/PACS2/TRPV1 axis in cardiomyocyte injury and LV dysfunction during ECS.
• To elucidate the mechanism by which this axis influences mitochondrial function and calcium flux.

Main Methods:

• Mice were exposed to -20 °C to simulate ECS.
• Manipulated miR-499-5p levels (overexpression and inhibition) and studied phosphofurin acidic cluster sorting protein 2 (PACS2) expression.
• Utilized cardiac-specific Pacs2 knock-in models.
• Assessed LV structure and function, mitophagy, mitochondrial energy metabolism, and endoplasmic reticulum-mitochondrial calcium flux via transient receptor potential cation channel subfamily V member 1 (TRPV1).

Main Results:

• ECS induced cardiomyocyte injury and LV dysfunction, associated with decreased miR-499-5p and PACS2 levels.
• Overexpression of miR-499-5p further inhibited mitochondrial function.
• Inhibition of miR-499-5p reversed ECS-induced cardiac deficits by upregulating PACS2.
• Cardiac-specific Pacs2 restoration normalized mitophagy and energy metabolism by enhancing ER-mitochondrial calcium flux through TRPV1.

Conclusions:

• The miR-499-5p/PACS2/TRPV1 axis is a key mediator of cardiac dysfunction during extreme cold stress.
• Modulating this axis, particularly by targeting miR-499-5p or enhancing PACS2, offers potential therapeutic strategies for preventing cold-induced heart disease.