Lymphotoxin-α is a novel adiponectin expression suppressor following myocardial ischemia/reperfusion.
Recent clinical observations demonstrate adiponectin (APN), an adipocytokine with potent cardioprotective actions, is significantly reduced following myocardial ischemia/reperfusion (MI/R). However, mechanisms responsible for MI/R-induced hypoadiponectinemia remain incompletely understood. Adult male mice were subjected to 30-min MI followed by varying reperfusion periods. Adipocyte APN mRNA and protein expression and plasma APN and TNFα concentrations were determined. APN expression/production began to decline 3 h after reperfusion (reaching nadir 12 h after reperfusion), returning to control levels 7 days after reperfusion. Plasma TNFα levels began to increase 1 h after reperfusion, peaking at 3 h and returning to control levels 24 h after reperfusion. TNFα knockout significantly increased plasma APN levels 12 h after reperfusion but failed to improve APN expression/production 72 h after reperfusion. In contrast, TNF receptor-1 (TNFR1) knockout significantly restored APN expression 12 and 72 h after reperfusion, suggesting that other TNFR1 binding cytokines contribute to MI/R-induced APN suppression. Among many cytokines increased after MI/R, lymphotoxin-α (LTα) was the only cytokine remaining elevated 24-72 h after reperfusion. LTα knockout did not augment APN levels 12 h post-reperfusion, but did so by 72 h. Finally, in vitro treatment of adipocytes with TNFα and LTα at concentrations seen in MI/R plasma additively inhibited APN expression/production in TNFR1-dependent fashion. Our study demonstrates for the first time that LTα is a novel suppressor of APN expression and contributes to the sustained hypoadiponectinemia following MI/R. Combining anti-TNFα with anti-LTα strategies may achieve the best effects restoring APN in MI/R patients.
Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Wayne Bond
WB
Lau
Yanqing
Y
Zhang
Jianli
J
Zhao
Baojiang
B
Liu
Xiaoliang
X
Wang
Yuexing
Y
Yuan
Theodore A
TA
Christopher
Bernard
B
Lopez
Erhe
E
Gao
Walter J
WJ
Koch
Xin L
XL
Ma
Yajing
Y
Wang
D041721:3T3-L1 Cells; D052242:Adiponectin / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation; D008233:Lymphotoxin-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D052242:Adiponectin; C499919:Adipoq protein, mouse; D008233:Lymphotoxin-alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha