Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure
Abstract
Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor α (PPAR-α) is a key regulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-α transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-α knockout mice in response to chronic pressure overload. We created a pressure-overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-α during heart failure using an inducible transgenic model. After 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-α expression in wild-type mice. We examined the effect of PPAR-α induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPAR-α induction with an increase in PPAR-α-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-α induction. Metabolic rates measured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-α. Myocardial high-energy phosphates were significantly preserved by PPAR-α induction. These results suggest that PPAR-α activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-α and modulation of FAO could be a promising therapeutic strategy for heart failure. NEW & NOTEWORTHY The present study demonstrates the role of PPAR-α activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-α preserved heart function, and myocardial energetics. Activating PPAR-α and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.
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The failing heart becomes metabolically inflexible with a decreased capacity to use fatty acids and an increased dependence on glucose metabolism.
“Conversely, the failing heart becomes metabolically inflexible with a decreased capacity to use fatty acids and an increased dependence on glucose metabolism (175).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [175]
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Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease
Smith, R. L., Soeters, M. R., Wüst, R. C. I., & Houtkooper, R. H. (2018) · Endocrine Reviews · doi:10.1210/er.2017-00211 · Cited by 787 · see citing works
- Authors
- Kaimoto, S., Hoshino, A., Ariyoshi, M., Okawa, Y., Tateishi, S., Ono, K., Uchihashi, M., Fukai, K., Iwai-Kanai, E., & Matoba, S.
- Affiliations
- Kyoto Prefectural University of Medicine (JP)
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kawaramachi-Hirokoji, Kyoto, Japan; and
- Corresponding author
- Matoba, Satoaki
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2017-02-01
- Volume
- 312
- Issue
- 2
- Pages
- H305-H313
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- OpenAlex
- W2566561968
- Cited by
- 103
- References
- 26
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 15 · 2023: 20 · 2022: 10 · 2021: 12 · 2020: 7 · 2019: 6 · 2018: 13 · 2017: 3
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (17K08609)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- PPARα, heart failure, pressure overload, transverse aortic constriction, fatty acid oxidation, myocardial energetics, myocardial fibrosis, high-energy phosphates, glucose oxidation, left ventricular function
- MeSH terms
- Animals, Aorta, Disease Models, Animal, Echocardiography, Energy Metabolism, Fatty Acids, Glucose, Heart Failure, Male, Mice, Transgenic, Myocardial Contraction, Myocardium, Oxidation-Reduction, Phosphates, Pyrimidines, Blotting, Western, Ventricular Dysfunction, Left, Reverse Transcriptase Polymerase Chain Reaction, PPAR alpha, Mice, Real-Time Polymerase Chain Reaction
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