Blocking cholesterol formation and turnover improves cellular and mitochondria function in murine heart microvascular...

Area of Science:

• Cardiovascular Science
• Cellular Bioenergetics
• Pharmacology

Background:

• Statins and PCSK9 inhibitors are key therapies for cardiovascular disease prevention.
• Their mechanisms involve lipid lowering and partially understood pleiotropic effects.
• This study investigates their impact on cardiac microvascular endothelial cells and cardiomyocytes.

Purpose of the Study:

• To analyze the effects of atorvastatin and a synthetic peptide PCSK9 inhibitor (PCSK9i) on cellular bioenergetics.
• To evaluate their impact on the function of microvascular endothelial cells and cardiomyocytes.
• To compare the efficacy of PCSK9i versus atorvastatin under normal and hypoxia-mimicking conditions.

Main Methods:

• Assessed mitochondrial function and abundance in H5V cells and HL-1 cells.
• Measured intracellular nucleotides, membrane potential, and cytoskeleton structure.
• Evaluated cell proliferation rates under normal and CoCl2-induced hypoxia-mimicking conditions.

Main Results:

• Under normal conditions, PCSK9i enhanced mitochondrial respiration, increased nucleotide levels, stabilized cytoskeleton, and promoted endothelial cell proliferation.
• Atorvastatin did not show these effects under normal conditions.
• Both atorvastatin and PCSK9i improved mitochondrial respiration and membrane potential under hypoxia-mimicking conditions.

Conclusions:

• Both atorvastatin and PCSK9i treatments positively impacted endothelial cell and cardiomyocyte bioenergetics.
• PCSK9i exhibited superior benefits compared to atorvastatin, particularly under normal physiological conditions.
• These findings highlight distinct cellular effects of lipid-lowering therapies beyond lipid reduction.