Dual peroxisome-proliferator-activated-receptor-α/γ activation inhibits SIRT1-PGC1α axis and causes cardiac...

Area of Science:

• Cardiovascular research
• Metabolic disease mechanisms
• Molecular pharmacology

Background:

• Dual peroxisome proliferator-activated receptor (PPAR)α/γ agonists were developed for type 2 diabetes and hyperlipidemia.
• These agonists have been associated with cardiac dysfunction and adverse effects.
• Understanding the mechanisms of cardiotoxicity is crucial for drug development.

Purpose of the Study:

• To investigate the mechanisms underlying the cardiotoxic effects of the dual PPARα/γ agonist tesaglitazar.
• To examine the impact of tesaglitazar on cardiac function, gene expression, and mitochondrial biology in mice.
• To evaluate the potential therapeutic role of SIRT1 activation in mitigating tesaglitazar-induced cardiotoxicity.

Main Methods:

• Tesaglitazar treatment in wild-type and diabetic (db/db) mice.
• Assessment of cardiac function, plasma lipids, and glucose levels.
• Analysis of cardiac gene expression, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and sirtuin 1 (SIRT1).
• Evaluation of mitochondrial abundance and acetylation of PGC1α.
• Pharmacological activation of PPARα/γ and SIRT1 (resveratrol) in mouse models.
• Studies in cardiomyocyte-specific Sirt1 knockout mice.

Main Results:

• Tesaglitazar treatment led to cardiac dysfunction in mice, despite improved plasma triglyceride and glucose levels.
• Cardiac PGC1α expression was significantly reduced, accompanied by increased PGC1α acetylation and decreased SIRT1 expression.
• Mitochondrial abundance was lower in tesaglitazar-treated mice.
• Combined PPARα and PPARγ activation mimicked these effects.
• Resveratrol-mediated SIRT1 activation attenuated tesaglitazar-induced cardiac dysfunction and improved mitochondrial respiration, except in cardiomyocyte-specific Sirt1-/- mice.

Conclusions:

• Dual PPARα/γ activation by drugs like tesaglitazar can cause cardiac dysfunction.
• This cardiotoxicity is linked to PGC1α suppression, increased PGC1α acetylation, and reduced mitochondrial abundance, potentially due to competing effects of PPARα and PPARγ.
• SIRT1 activation represents a potential therapeutic strategy to counteract the cardiotoxic effects of these dual agonists.