Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice
Ni-Huiping Son, … , Li-Shin Huang, Ira J. Goldberg
Ni-Huiping Son, … , Li-Shin Huang, Ira J. Goldberg
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2791-2801. https://doi.org/10.1172/JCI30335.
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Research Article Metabolism

Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice

Abstract

Three forms of PPARs are expressed in the heart. In animal models, PPARγ agonist treatment improves lipotoxic cardiomyopathy; however, PPARγ agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARγ on heart function, we created transgenic mice expressing PPARγ1 in the heart via the cardiac α–myosin heavy chain (α-MHC) promoter. PPARγ1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARα-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARγ1-transgenic mice developed a dilated cardiomyopathy associated with increased lipid and glycogen stores, distorted architecture of the mitochondrial inner matrix, and disrupted cristae. Thus, while PPARγ agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.

Authors

Ni-Huiping Son, Tae-Sik Park, Haruyo Yamashita, Masayoshi Yokoyama, Lesley A. Huggins, Kazue Okajima, Shunichi Homma, Matthias J. Szabolcs, Li-Shin Huang, Ira J. Goldberg

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Figure 1

Construct and gene expression in PPARγ1-transgenic mice.

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Construct and gene expression in PPARγ1-transgenic mice. (A) Diagram of ...
(A) Diagram of PPARγ1 genomic locus and PPARγ1 construct design. The α-MHC promoter was used to drive PPARγ1 cDNA expression. Black boxes indicate exons that are numbered. PCR primers are indicated. Boxes A1 and A2 indicate PPARγ1-specific exons. (B) Cardiac-specific MHC-PPARγ1 expression. RT-PCR analysis of RNA was performed in 3-month-old MHC-PPARγ1L male mice using primer A: 5ι end specific to α-MHC promoter exon 2 and 3′ end specific to PPARγ1 cDNA nucleotides 173–192. (C) Heart expression of total PPARγ mRNA (both endogenous gene and transgene) in MHC-PPARγ1L and MHC-PPARγ1H male mice was quantified by qRT-PCR. Primer C was used for PCR amplification. Data are shown as mean ratio (±SD; n = 5 in each group) corrected for 18S rRNA. ***P < 0.001 for MHC-PPARγ1 mice versus control mice. (D) Nuclear protein (30 μg) from heart tissues of 4- and 8-month-old MHC-PPARγ1L and 4-month-old MHC-PPARγ1H mice and their littermate controls was analyzed by Western blot using polyclonal PPARγ antibody. Western blot for lamin B1 is shown as a control. (E) Bands were quantified using Molecular Analysis Software. Data were normalized to values for littermate controls (set at 1.0), and normalized units of expression are shown (±SD; n = 3 in each group). **P < 0.01; ***P < 0.001 for MHC-PPARγ1 versus control mice. C, littermate control; Tg, transgenic MHC-PPARγ1 mouse; PA, poly(A) site.