Leptin induces hypertrophy through activating the peroxisome proliferator-activated receptor α pathway in cultured neonatal rat cardiomyocytes.
1. Our previous study has shown that leptin induces cardiomyocyte hypertrophy; however, the mechanisms are poorly understood. Recent studies have shown that peroxisome proliferator-activated receptor α (PPARα) activation might be responsible for pathological remodeling and severe cardiomyopathy. Leptin, as an endogenous activator of PPARα, regulates energy metabolism through activating PPARα in many cells. Therefore, we hypothesized that leptin induces cardiomyocyte hypertrophy through activating the cardiac PPARα pathway. 2. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of PPARα on hypertrophy. The selective PPARα antagonist GW6471 concentration-dependently decreased atrial natriuretic factor mRNA expression by 23%, 36%, 44% and 59%, and significantly decreased total RNA levels, protein synthesis and cell surface areas, all of which were elevated by 72h of leptin treatment. The augmentation of reactive oxygen species levels in leptin treated cardiomyocytes was reversed by 0.1-10μmol/L GW6471 (40%, 52% and 58%). After 24h of treatment, leptin concentration-dependently enhanced mRNA expression by 7%, 93%, 100% and 256%, and protein expression by 31.2%, 64.2%, 143% and 199%, and the activity of PPARα. Meanwhile, cardiomycytes receiving 72h of treatment with the PPARα agonist, fenofibrate, concentration-dependently increased total RNA levels, atrial natriuretic factor mRNA expression, protein synthesis and cell surface area. Treatment of fenofibrate for 4 h also elevated oxygen species levels in a concentration-dependent manner. 3. In conclusion, these findings show that leptin induces hypertrophy through the activation of the PPARα pathway in cultured neonatal rat cardiomyocytes.
Hou
Ning
N
Department of Pharmacology, Guangzhou Medical University, China.
Luo
Miao-Shan
MS
Liu
Shi-Ming
SM
Zhang
Hai-Ning
HN
Xiao
Qing
Q
Sun
Pu
P
Zhang
Gen-Shui
GS
Luo
Jian-Dong
JD
Chen
Min-Sheng
MS
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism; D018929:Cell Culture Techniques; D049108:Cell Enlargement / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
C449302:GW 6471; D020738:Leptin; D010080:Oxazoles; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D014443:Tyrosine