Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice
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
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
View: Text | PDF
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

×

Figure 3

Increased heart lipid accumulation in MHC-PPARγ1 mice.

Options: View larger image (or click on image) Download as PowerPoint
Increased heart lipid accumulation in MHC-PPARγ1 mice. (A) Heart TG (lef...
(A) Heart TG (left panel) and FFA content (right panel) was significantly increased in MHC-PPARγ1L transgenic mice (n = 7 for each group). (B) Oil red O staining showed an abundance of neutral lipid droplets randomly scattered throughout the cytoplasm of cardiomyocytes in MHC-PPARγ1L female mice (right panel) after 24-hour fasting (original magnification, ×400). (C) Oil red O staining was quantified using Molecular Analysis Software (n = 3 in each group). Data were normalized to values for littermate controls (set as 1.0). (D). Electron micrographs (original magnification, ×15,000) of myocardial tissue showed a large increase in lipid droplets within the sarcoplasm of cardiomyocytes in MHC-PPARγ1L male mice (right panel) compared with littermates (left panel). All of these lipid droplets were located adjacent to mitochondria, with distortion of the mitochondrial contours. (E) Electron micrographs (original magnification, ×50,000) detailed distorted architecture of the mitochondrial inner matrix with electron lucent foci (arrows) in MHC-PPARγ1L mice, and in some areas the cristae were disrupted. (F) [14C-TG]VLDL uptake into heart of MHC-PPARγ1L male mice and littermate control mice at 8 months of age (n = 6 per group). LD, lipid droplet; M, mitochondria. Data are shown as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 compared with littermate controls. DPM, decays per minute.