Cited by 110Peroxisome Proliferator-Activated ReceptorsMitochondrial Function and PathologyAdipose Tissue and Metabolism

Peroxisome Proliferator-Activated Receptor δ Is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult Heart

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Wang, Peiyong, Liu, Jian, Li, Yuquan, Wu, Sijie, Luo, Jinwen, Yang, Huan, Subbiah, Ramasamy, Chatham, John +2 more·2010·Circulation Research

Abstract

Rationale: Peroxisome proliferator-activated receptors (PPARs) (α, γ, and δ/β) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPARδ deficiency in mice leads to depressed myocardial fatty acid oxidation, bioenergetics, and premature death with lipotoxic cardiomyopathy. Objective: To explore the essential role of PPARδ in the adult heart. Methods and Results: We investigated the consequences of inducible short-term PPARδ knockout in the adult mouse heart. In addition to a substantial transcriptional downregulation of lipid metabolic proteins, short-term PPARδ knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase and manganese superoxide dismutase, leading to increased oxidative damage to the heart. Moreover, expression of key mitochondrial biogenesis determinants such as PPARγ coactivator-1 were substantially decreased in the short-term PPARδ deficient heart, concomitant with a decreased mitochondrial DNA copy number. Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPARδ knockout hearts. Consequently, PPARδ deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy. Conclusions: PPARδ is an essential regulator of cardiac mitochondrial protection and biogenesis and PPARδ activation can be a potential therapeutic target for cardiac disorders.

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Authors
Wang, P., Liu, J., Li, Y., Wu, S., Luo, J., Yang, H., Subbiah, R., Chatham, J., Zhelyabovska, O., & Yang, Q.
Affiliations
University of Alabama at Birmingham (US)
Corresponding author
Yang, Qinglin
Venue
Circulation Research
Published
2010-03-19
Volume
106
Issue
5
Pages
911-919
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
OpenAlex
W2072261695
Cited by
110
References
46
Citations by year
2025: 4 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 5 · 2018: 12 · 2017: 11 · 2016: 6 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 12
FWCI
3.39
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01hl084456-06)
  • National Heart, Lung, and Blood Institute (R01-HL084456, 1R01 HL084456, R01HL085499)
  • National Center for Complementary and Integrative Health (R21AT003734)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
PPARδ, mitochondrial protection, oxidative stress, superoxide dismutase, PGC-1, mitochondrial DNA copy number, fatty acid oxidation, cardiac hypertrophy, nuclear receptors, transcriptional regulation
MeSH terms
Superoxide Dismutase-1, Superoxide Dismutase 2, Aging, Animals, Antioxidants, Cells, Cultured, DNA, Mitochondrial, Energy Metabolism, Glucose, Cardiomegaly, Homeostasis, Mice, Inbred C57BL, Mitochondria, Heart, Oxidation-Reduction, RNA, Messenger, Superoxide Dismutase, Transcription, Genetic, Gene Expression Regulation, Enzymologic, Mice, Knockout, Oxidative Stress, Ventricular Dysfunction, Left, Palmitic Acid, Myocytes, Cardiac, PPAR delta, Lipid Metabolism, Mice

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