期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 26, 页码 10086-10091出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0603615103
关键词
cardiac metabolism; mitochondria; transcription
资金
- NHLBI NIH HHS [K08 HL079172, HL 079172, HL 077543, R01 HL077543] Funding Source: Medline
- NIDDK NIH HHS [DK 61562, R01 DK054477, R01 DK061562, R56 DK054477, DK 54477] Funding Source: Medline
Heart failure is accompanied by important defects in metabolism. The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) is a powerful regulator of mitochondrial biology and metabolism. PGC-1 alpha and numerous genes regulated by PGC-1 alpha are repressed in models of cardiac stress, such as that generated by transverse aortic constriction (TAC). This finding has suggested that PGC-1 alpha 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-1 alpha 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-1a and many of its target genes, recapitulating the findings in vivo in response to TAC. Importantly, introduction of ectopic PGC-1 alpha can reverse the repression of most of these genes by epinephrine. Together, these data indicate that endogenous PGC-1 alpha serves a cardioprotective function and suggest that repression of PGC-1 alpha significantly contributes to the development of heart failure. Moreover, the data suggest that elevating PGC-1 alpha activity may have therapeutic potential in the treatment of heart failure.
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