Therapeutic effect of midkine on cardiac remodeling in infarcted rat hearts.
BACKGROUND
Midkine is expressed in the developing fetus and in adult organs stressed by ischemia, but its physiologic role in ischemic organs is poorly understood. Here we investigated the effect of midkine on cardiac remodeling after ischemia caused by myocardial infarction.


METHODS
The expression pattern of the endogenous midkine gene in rat heart was evaluated by real-time polymerase chain reaction for 2 weeks after myocardial infarction. To investigate its effect, recombinant midkine was injected into hearts 2 weeks after myocardial infarction, and cardiac functions were monitored by echocardiography. Six weeks later, the hearts were removed, and the areas of infarcted and viable tissue and the extent of cardiomyocyte hypertrophy were determined histologically.


RESULTS
The midkine gene was strongly upregulated in the infarcted myocardium, but this upregulation lasted less than 2 weeks. Cardiac remodeling was significantly and dose-dependently attenuated by midkine treatment. The midkine treatment also increased collagen accumulation and facilitated angiogenesis in the infarcted area, and the viable muscle area after myocardial infarction dose-dependently increased. Despite this increase of viable muscle area, the midkine-treated hearts showed significantly less cardiomyocyte hypertrophy than vehicle-treated hearts, suggesting midkine had prevented chronically ischemic cells from dying and dropping out by angiogenesis.


CONCLUSIONS
Our results indicate midkine can attenuate cardiac remodeling after myocardial infarction, and suggest midkine has therapeutic potential for subacute myocardial infarction.
Fukui
Shinya
S
Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Kitagawa-Sakakida
Satoru
S
Kawamata
Sin
S
Matsumiya
Goro
G
Kawaguchi
Naomasa
N
Matsuura
Nariaki
N
Sawa
Yoshiki
Y
D000818:Animals; D001707:Biopsy, Needle; D016207:Cytokines / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015150:Echocardiography, Doppler; D015316:Genetic Therapy / Q000379:methods; D007150:Immunohistochemistry; D015552:Injections, Intralesional; D008297:Male; D000078792:Midkine; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy*; D016133:Polymerase Chain Reaction; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D012016:Reference Values; D012680:Sensitivity and Specificity; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
D016207:Cytokines; D000078792:Midkine