Serum midkine predicts cardiac events in patients with heart failure

Background: Recent our clinical work demonstrated that placental growth factor (PlGF), a member of VEGF family, is rapidly produced within infarct myocardial tissue, and the plasma level of PlGF is positively correlated with the number of monocytes and CD34-positive cells, and improvement of left ventricular function. However, therapeutic effects of PlGF onMI are not understood. Methods and results: One day before ligation of coronary artery, recombinant human PlGF (rhPlGF) (1 μg) was infused into the peritoneal cavity of C57BL/6 mice through subcutaneously implanted osmotic mini pump until 2 days after the ligation. After 28 days, survival rate was significantly higher in rhPlGF-treated group (70.0%) than PBS-treated group (33.3%) (pb0.05). Seven days after MI, the infarct area, stained by 1.5% TTC (2,3,5-triphenyltetrazolium chloride), was smaller in rhPlGF-treated group (4.25±2.04 mm) than PBS-treated group (5.95±1.54 mm), and it indicates that exogenous PlGF suppressed cardiac remodeling. Echocardiography also revealed that left ventricular diastolic diameter was decreased (rhPlGF: 4.50±0.46 mm, PBS: 5.14±0.38 mm, pb0.01), and ejection fraction was increased in rhPlGF-treated group (rhPlGF: 40.6+9.17%, PBS: 25.7+7.23%, pb0.01). Histological analysis showed that both CD31-positive vascular endothelial cells (rhPlGF: 644.6+ 90.54/mm, PBS: 459.0+ 73.89/mm, pb0.01) and α-smooth muscle actin-positive vessels (rhPlGF: 31.6+7.20/mm, PBS: 23.5+7.41/mm, pb0.01) was increased at infarct area. Conclusion: rhPlGF treatment preserved left ventricular function and inhibited post-infarct remodeling by enhancing neovascularization and arteriogenesis, resulting in improvement of survival rate after myocardial infarction.