The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome.

Abstract

BACKGROUND:

The PGC-1α/PPAR axis has been proposed as a potential therapeutic target for several metabolic disorders. The aim was to evaluate the efficacy of the pan-PPAR agonist, bezafibrate, in tafazzin knockdown mice (TazKD), a mouse model of Barth syndrome that exhibits age-dependent dilated cardiomyopathy with left ventricular (LV) dysfunction.

RESULTS:

The effect of bezafibrate on cardiac function was evaluated by echocardiography in TazKD mice with or without beta-adrenergic stress. Adrenergic stress by chronic isoproterenol infusion exacerbates the cardiac phenotype in TazKD mice, significantly depressing LV systolic function by 4.5 months of age. Bezafibrate intake over 2 months substantially ameliorates the development of LV systolic dysfunction in isoproterenol-stressed TazKD mice. Without beta-adrenergic stress, TazKD mice develop dilated cardiomyopathy by 7 months of age. Prolonged treatment with suprapharmacological dose of bezafibrate (0.5% in rodent diet) over a 4-month period effectively prevented LV dilation in mice isoproterenol treatment. Bezafibrate increased mitochondrial biogenesis, however also promoted oxidative stress in cardiomyocytes. Surprisingly, improvement of systolic function in bezafibrate-treated mice was accompanied with simultaneous reduction of cardiolipin content and increase of monolysocardiolipin levels in cardiac muscle.

CONCLUSIONS:

Thus, we demonstrate that bezafibrate has a potent therapeutic effect on preventing cardiac dysfunction in a mouse model of Barth syndrome with obvious implications for treating the human disease. Additional studies are needed to assess the potential benefits of PPAR agonists in humans with Barth syndrome.

• Authors: Yan Huang, Corey Powers, Victoria Moore, Caitlin Schafer, Mindong Ren, Colin K L Phoon, Jeanne F James, Alexander V Glukhov, Sabzali Javadov, Frédéric M Vaz, John L Jefferies, Arnold W Strauss, Zaza Khuchua
• Journal: Orphanet journal of rare diseases (Orphanet J Rare Dis) Vol. 12 Issue 1 Pg. 49 (03 09 2017) ISSN: 1750-1172 [Electronic] England
• PMID: 28279226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiolipins
• Peroxisome Proliferator-Activated Receptors
• Bezafibrate

Topics

• Animals
• Barth Syndrome (drug therapy, metabolism)
• Bezafibrate (therapeutic use)
• Blotting, Western
• Cardiolipins (metabolism)
• Cardiomyopathies (drug therapy, metabolism)
• Disease Models, Animal
• Echocardiography
• Female
• Male
• Mice
• Peroxisome Proliferator-Activated Receptors (agonists)
• Polymerase Chain Reaction