Cardiac functional improvement in rats with myocardial infarction by up-regulating cardiac myosin light chain kinase with neuregulin.
OBJECTIVE
Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in experimental heart failure models, but the underlying mechanism remains largely unknown. In this study, we evaluated whether rhNRG-1 could improve cardiac function via the cardiac myosin light chain kinase/myosin light chain 2 ventricular (cMLCK/MLC-2v) pathway in rats with myocardial infarction (MI).


RESULTS
Rats with MI were intravenously infused with rhNRG-1 (5 µg/kg/h) for 7 days through osmotic pumps. The mechanism of action of rhNRG-1 was investigated by assaying the non-infarcted myocardium with gene chips. The cMLCK expression, phosphorylated MLC-2v and cardiac function were significantly up-regulated, as assessed by real-time PCR, Western blot and echocardiography, in those animals treated with rhNRG-1. Moreover, the restoration of rhNRG-1-induced sarcomeric organization in serum-free cultured neonatal rat cardiomyocytes with rhNRG-1 was inhibited by cMLCK RNA interference or ML-7, an inhibitor of MLCKs. Adenovirus containing the rat cMLCK coding region was injected into non-infarcted myocardium, and cardiac function was monitored using echocardiography and a haemodynamic machine. The dP/dt and fractional shortening decreasing significantly after MI, and improved by 15.7 and 32.1%, respectively, following local cMLCK application (all P < 0.05).


CONCLUSIONS
Our results suggest that cMLCK is a downstream effector of rhNRG-1 involved in rhNRG-1-induced cardiac function improvement, and that myocardial cMLCK up-regulation can improve cardiac function in rats with MI.
Gu
Xinghua
X
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai 200032, PR China.
Liu
Xifu
X
Xu
Danling
D
Li
Xinyan
X
Yan
Ming
M
Qi
Ying
Y
Yan
Weihai
W
Wang
Wenqing
W
Pan
Jing
J
Xu
Yabei
Y
Xi
Bing
B
Cheng
Leilei
L
Jia
Jianguo
J
Wang
Keqiang
K
Ge
Junbo
J
Zhou
Mingdong
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D024722:Cardiac Myosins / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology*; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1 / Q000008:administration & dosage*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage; D020127:Recovery of Function; D012518:Sarcomeres / Q000201:enzymology; D014162:Transfection; D014463:Ultrasonography; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects*
D018994:Myosin Light Chains; C094131:NRG1 protein, human; D020890:Neuregulin-1; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C107184:myosin light chain 2; D009219:Myosin-Light-Chain Kinase; D024722:Cardiac Myosins