Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2006 Jun 27;103(26):10086-91.
doi: 10.1073/pnas.0603615103. Epub 2006 Jun 14.

Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha

Zoltan Arany  1 , Mikhail Novikov, Sherry Chin, Yanhong Ma, Anthony Rosenzweig, Bruce M Spiegelman
Affiliations

Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha

Zoltan Arany et al. Proc Natl Acad Sci U S A. .

Abstract

Heart failure is accompanied by important defects in metabolism. The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) is a powerful regulator of mitochondrial biology and metabolism. PGC-1alpha and numerous genes regulated by PGC-1alpha are repressed in models of cardiac stress, such as that generated by transverse aortic constriction (TAC). This finding has suggested that PGC-1alpha 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-1alpha 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-1alpha and many of its target genes, recapitulating the findings in vivo in response to TAC. Importantly, introduction of ectopic PGC-1alpha can reverse the repression of most of these genes by epinephrine. Together, these data indicate that endogenous PGC-1alpha serves a cardioprotective function and suggest that repression of PGC-1alpha significantly contributes to the development of heart failure. Moreover, the data suggest that elevating PGC-1alpha activity may have therapeutic potential in the treatment of heart failure.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Cardiac dysfunction in response to TAC in PGC-1α−/− (KO) mice. PGC-1α WT and KO mice underwent TAC as described in Methods. (A) Average values for the indicated echocardiographic parameter from WT and KO mice during the 2 months after TAC (n = 5 in each group). Error bars indicate SEM. (B) Sample 2D echocardiographs from WT and KO mice without TAC (Upper) or 2 months after TAC (Lower).
Fig. 2.
Fig. 2.
PGC-1α−/− (KO) mice develop dilated cardiomyopathy in response to TAC. Hearts from the animals described in Fig. 1 were excised 2 months after TAC. (A) Photographs of sample WT and KO hearts with and without TAC. (B) Low-magnification views of hematoxylin/eosin stains of transverse sections of the same hearts as in A. (C) Average weights of hearts from all mice described in Fig. 1. (D) Sample higher-magnification views of trichrome stains from the same hearts as in B. Blue indicates the accumulation of extracellular matrix or fibrosis. (Magnifications: ×20.)
Fig. 3.
Fig. 3.
PGC-1α−/− (KO) mice develop clinical heart failure in response to TAC. (A) Average weights of lungs from WT and PGC-1α KO mice without or 2 months after TAC (n = 5 in each group). (B) mRNA expression of β-myosin heavy chain (β-MHC) and atrial natriuretic factor (ANF) in the same mice as in A. (C) Mouse body weight before and 2 months after TAC in WT and PGC-1α KO mice (n = 3). Error bars indicate SEM.
Fig. 4.
Fig. 4.
PGC-1α, genes regulated by PGC-1α, and activities of the electron transport chain, in WT and PGC-1α−/− hearts after TAC. (A) mRNA expression of representative genes of mitochondrial electron transport chain (cycs, nduf5, cox5b, and atp5o, Top), fatty acid metabolism (cd36, mcad, cpt1, and cpt2, Middle), and transcriptional regulation (PGC-1α, PGC-1β, PRC, and ERRα, Bottom) in a subset of the mice described in Fig. 1 (n = 3). ∗, P < 0.05 compared with WT. ∗∗, P < 0.05 compared with KO. (B) Views of sample frozen sections, cut transversely from the same hearts as in Fig. 2 and stained for SDH and COX activity. (Magnification: ×10.)
Fig. 5.
Fig. 5.
PE inhibits PGC-1α and PGC-1α target genes in cardiomyocytes, and ectopic expression of PGC-1α rescues the inhibition of target genes. (A) mRNA expression of representative genes of mitochondrial electron transport chain (cox8h, nduf5, cox5b, atp5o, and ant) and fatty acid metabolism (mcad, cpt1, cpt2, and ppara) in primary NRVMs 48 h after treatment with PE (+, 100 μM; ++, 300 μM). ∗, P < 0.05 compared with untreated control. (B) NRVMs were infected (multiplicity of infection ≈5–10) with replication-incompetent adenovirus encoding for either GFP (as control) or PGC-1α and GFP. Forty-eight hours later, the cells were either left untreated or treated with 100 μM PE (+PE) for another 48 h. mRNA was then harvested. Expression of representative genes of mitochondrial electron transport chain (cycs, nduf5, cox5b, atp5o, and ant), mitochondrial protection against reactive oxygen species (sod2), and nuclear receptors involved in regulating these genes (ppara and erra) is indicated. Error bars indicate SEM.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Thom T., Haase N., Rosamond W., Howard V. J., Rumsfeld J., Manolio T., Zhang Z. J., Flegal K., O’Donnell C., Kittner S., et al. Circulation. 2006;113:e85. - PubMed
    1. Jessup M., Brozena S. N. Engl. J. Med. 2003;348:2007–2018. - PubMed
    1. Pfeffer M. A., Braunwald E. Circulation. 1990;81:1161–1172. - PubMed
    1. Ingwall J. S., Weiss R. G. Circ. Res. 2004;95:135–145. - PubMed
    1. Taegtmeyer H., Wilson C. R., Razeghi P., Sharma S. Ann. N.Y. Acad. Sci. 2005;1047:208–218. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources

-