Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice.
Three forms of PPARs are expressed in the heart. In animal models, PPARgamma agonist treatment improves lipotoxic cardiomyopathy; however, PPARgamma agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARgamma on heart function, we created transgenic mice expressing PPARgamma1 in the heart via the cardiac alpha-myosin heavy chain (alpha-MHC) promoter. PPARgamma1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARalpha-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARgamma1-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 PPARgamma agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.
Son
Ni-Huiping
NH
Division of Preventive Medicine and Nutrition, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Park
Tae-Sik
TS
Yamashita
Haruyo
H
Yokoyama
Masayoshi
M
Huggins
Lesley A
LA
Okajima
Kazue
K
Homma
Shunichi
S
Szabolcs
Matthias J
MJ
Huang
Li-Shin
LS
Goldberg
Ira J
IJ
D000375:Aging / Q000235:genetics; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D024723:Ventricular Myosins / Q000235:genetics