Adiponectin: an indispensable molecule in rosiglitazone cardioprotection following myocardial infarction.
BACKGROUND
Patients treated with peroxisome proliferator-activated receptor (PPAR)-gamma agonist manifest favorable metabolic profiles associated with increased plasma adiponectin (APN). However, whether increased APN production as a result of PPAR-gamma agonist treatment is an epiphenomenon or is causatively related to the cardioprotective actions of PPAR-gamma remains unknown.


OBJECTIVE
To determine the role of APN in rosiglitazone (RSG) cardioprotection against ischemic heart injury.


RESULTS
Adult male wild-type (WT) and APN knockdown/knockout (APN(+ or -) and APN(- or -)) mice were treated with vehicle or RSG (20 mg/kg per day), and subjected to coronary artery ligation 3 days after beginning treatment. In WT mice, RSG (7 days) significantly increased adipocyte APN expression, elevated plasma APN levels (2.6-fold), reduced infarct size (17% reduction), decreased apoptosis (0.23 + or - 0.02% versus 0.47 + or - 0.04% TUNEL-positive in remote nonischemic area), attenuated oxidative stress (48.5% reduction), and improved cardiac function (P<0.01). RSG-induced APN production and cardioprotection were significantly blunted (P<0.05 versus WT) in APN(+ or -), and completely lost in APN(- or -) (P>0.05 versus vehicle-treated APN(- or -) mice). Moreover, treatment with RSG for up to 14 days significantly improved the postischemic survival rate of WT mice (P<0.05 versus vehicle group) but not APN knockdown/knockout mice.


CONCLUSIONS
The cardioprotective effects of PPAR-gamma agonists are critically dependent on its APN stimulatory action, suggesting that under pathological conditions where APN expression is impaired (such as advanced type 2 diabetes), the harmful cardiovascular effects of PPAR-gamma agonists may outweigh its cardioprotective benefits.
Tao
Ling
L
Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, 15 West Changle Rd, Xian, China, 710032. Lingtao2006@gmail.com
Wang
Yajing
Y
Gao
Erhe
E
Zhang
Hangxiang
H
Yuan
Yuexing
Y
Lau
Wayne B
WB
Chan
Lawrence
L
Koch
Walter J
WJ
Ma
Xin L
XL
D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006334:Heart Function Tests; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D016019:Survival Analysis; D045162:Thiazolidinediones / Q000494:pharmacology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D052242:Adiponectin; D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone