Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy.
Fatty acid oxidation (FAO) is a primary energy source for meeting the heart's energy requirements. Peroxisome proliferator-activated receptor-delta (PPAR-delta) may have important roles in FAO. But it remains unclear whether PPAR-delta is required for maintaining basal myocardial FAO. We show that cre-loxP-mediated cardiomyocyte-restricted deletion of PPAR-delta in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. These mice have cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy and congestive heart failure with reduced survival. Thus, chronic myocardial PPAR-delta deficiency leads to lipotoxic cardiomyopathy. Together, our data show that PPAR-delta is a crucial determinant of constitutive myocardial FAO and is necessary to maintain energy balance and normal cardiac function. We suggest that PPAR-delta is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases.
Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, USA.
Lihong
L
Cheng
Guoliang
G
Ding
Qianhong
Q
Qin
Yao
Y
Huang
William
W
Lewis
Nu
N
He
Ronald M
RM
Evans
Michael D
MD
Schneider
Florence A
FA
Brako
Yan
Y
Xiao
Yuqing E
YE
Chen
Qinglin
Q
Yang
D055372:AMP-Activated Protein Kinases; D000704:Analysis of Variance; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology*; D005227:Fatty Acids / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000172:deficiency* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
D005227:Fatty Acids; D009097:Multienzyme Complexes; D047494:PPAR delta; D014280:Triglycerides; D008316:Malonyl Coenzyme A; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose