PPARγ Regulates Mitochondrial Structure and Function and Human Pulmonary Artery Smooth Muscle Cell Proliferation

Area of Science:

• Mitochondrial biology and metabolic regulation in cardiovascular disease.

Background:

• Pulmonary hypertension (PH) involves metabolic issues driving vascular remodeling and cell proliferation.
• Decreased peroxisome proliferator-activated receptor γ (PPARγ) is linked to increased pulmonary artery smooth muscle cell (PASMC) proliferation.
• PPARγ, with coactivator 1α (PGC1α), regulates mitochondrial function.

Purpose of the Study:

• To investigate how reduced PPARγ impacts human PASMC (HPASMC) mitochondrial structure and function.
• To determine if PPARγ or PGC1α depletion stimulates HPASMC proliferation.

Main Methods:

• HPASMCs were exposed to hypoxia and treated with a PPARγ antagonist or siRNA against PPARγ or PGC1α.
• Assessed were HPASMC proliferation, mRNA/protein levels, mitochondrial H2O2, mass, fragmentation, and bioenergetics.

Main Results:

• Hypoxia or depletion of PPARγ/PGC1α increased HPASMC proliferation.
• Mitochondrial dysfunction, including increased H2O2, reduced mass, fragmentation, and impaired bioenergetics, was observed.
• Overexpression of PGC1α reversed hypoxia-induced cellular changes.

Conclusions:

• Loss of PPARγ impairs PGC1α, leading to mitochondrial structural and functional derangements that drive PASMC proliferation.
• These findings reveal new mechanisms in PH pathogenesis.
• Activating PPARγ presents a potential therapeutic strategy for PH.