Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α
Open accessAbstract
Heart failure is accompanied by important defects in metabolism. The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) is a powerful regulator of mitochondrial biology and metabolism. PGC-1α and numerous genes regulated by PGC-1α are repressed in models of cardiac stress, such as that generated by transverse aortic constriction (TAC). This finding has suggested that PGC-1α repression may contribute to the maladaptive response of the heart to chronic hemodynamic loads. We show here that TAC in mice genetically engineered to lack PGC-1α leads to accelerated cardiac dysfunction, which is accompanied by signs of significant clinical heart failure. Treating cardiac cells in tissue culture with the catecholamine epinephrine leads to repression of PGC-1α and many of its target genes, recapitulating the findings in vivo in response to TAC. Importantly, introduction of ectopic PGC-1α can reverse the repression of most of these genes by epinephrine. Together, these data indicate that endogenous PGC-1α serves a cardioprotective function and suggest that repression of PGC-1α significantly contributes to the development of heart failure. Moreover, the data suggest that elevating PGC-1α activity may have therapeutic potential in the treatment of heart failure.
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Repression of PGC-1α or PGC-1β decreases mitochondrial biogenesis and function, causes cardiomyopathy, and impairs de novo glucose production.
“Previous work has established that repression of either or both co-activators (PGC-1α or PGC-1β) decreases mitochondrial biogenesis and function, elicits cardiomyopathy and impairs de novo glucose production23-25.”
From Telomere dysfunction induces metabolic and mitochondrial compromise (2011) · cites this paper as [23]
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- Authors
- Arany, Z., Novikov, M., Chin, S., Ma, Y., Rosenzweig, A., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Spiegelman, Bruce M.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-06-27
- Volume
- 103
- Issue
- 26
- Pages
- 10086-10091
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1502510
- OpenAlex
- W2103634232
- Cited by
- 374
- References
- 48
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 11 · 2023: 20 · 2022: 21 · 2021: 32 · 2020: 23 · 2019: 18 · 2018: 18 · 2017: 20 · 2016: 15 · 2015: 32 · 2014: 27 · 2013: 15 · 2012: 25
- FWCI
- 6.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Heart, Lung, and Blood Institute (K08HL079172, HL-077543, HL079172, R01HL077543)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK54477, R56DK054477, R01DK061562, R01DK054477, DK 61562)
- 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
- PGC-1α, heart failure, transverse aortic constriction, cardiac hypertrophy, epinephrine, mitochondrial metabolism, transcriptional repression, cardioprotection, cardiac dysfunction, heart failure treatment
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Aorta, Cardiac Output, Low, Constriction, Pathologic, Epinephrine, Gene Expression Regulation, Mutation, Transcription Factors, Trans-Activators, Down-Regulation, Mice, Knockout, Myocytes, Cardiac, Mice
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