Adenoviral gene transfer of sphingosine kinase 1 protects heart against ischemia/reperfusion-induced injury and attenuates its postischemic failure.
Sphingosine kinase 1 (SPK1) has been identified as a central mediator of ischemia preconditioning and plays a protective role in ischemia/reperfusion (I/R)-induced cardiomyocyte death. In the present study, we investigated the protective effect of adenovirus-mediated SPK1 gene (Ad-SPK1) transfer on I/R-induced cardiac injury, and evaluated its therapeutic action on postinfarction heart failure. Cardiac SPK1 activity was increased about 5-fold by injection of Ad-SPK1, compared with injection of adenovirus carrying the green fluorescent protein gene (Ad-GFP). A more potent performance and a lower incidence of arrhythmia were observed in Ad-SPK1-injected hearts during the reperfusion period, compared with Ad-GFP-injected hearts. An enzymatic activity assay showed that creatine kinase release was also less in Ad-SPK1-injected hearts. To investigate the therapeutic action of the SPK1 gene on postischemic heart failure, the left anterior descending branch of the coronary artery in Wistar rats was ligated after direct intramyocardial injection of Ad-SPK1 or Ad-GFP as a control. Ad-SPK1 injection significantly preserved cardiac systolic and diastolic function, as evidenced by left ventricular (LV) systolic pressure, LV end-diastolic pressure, and peak velocity of contraction (dP/dt). The LV morphometric parameters of Ad-SPK1-treated animals were also preserved. In addition, SPK1 gene delivery significantly enhanced angiogenesis and reduced fibrosis. These results demonstrate that adenovirus-mediated SPK1 gene transfer could efficiently prevent I/R-induced myocardial injury and attenuate postischemic heart failure. Thus, SPK1 gene delivery would be a novel strategy for the treatment of coronary heart disease.
Duan
Hai-Feng
HF
Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, People's Republic of China.
Wang
Hong
H
Yi
Jun
J
Liu
Hong-Jun
HJ
Zhang
Qun-Wei
QW
Li
Li-Bing
LB
Zhang
Tao
T
Lu
Ying
Y
Wu
Chu-Tse
CT
Wang
Li-Sheng
LS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000517:prevention & control; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D009200:Myocardial Contraction / Q000235:genetics; D017202:Myocardial Ischemia / Q000150:complications / Q000628:therapy; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000821:virology; D018919:Neovascularization, Physiologic / Q000235:genetics; D009924:Organ Culture Techniques; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000235:genetics; D000099157:Sphingosine Kinase
D003402:Creatine Kinase; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase