Abstract 11729: Midkine Exacerbates Cardiac Hypertrophy and Remodeling in Response to Pressure Overload
Midkine (MK) is a heparin-binding growth factor having various functions such as promotion of inflammatory cell migration and anti-apoptotic effect through mitogen-activated protein kinase (MAPK) activation. We reported that serum MK level was increased in patients with heart failure and was independently associated with adverse cardiac events. The aim of this study was to examine the role of MK in cardiac hypertrophy and remodeling. We generated transgenic mouse with cardiac specific overexpression of MK (MK-TG) using α-myosin heavy chain promoter. Transverse aortic constriction (TAC) or sham operation were performed in MK-TG and wild-type (WT) mice. After 4 weeks of TAC, the ratio of left ventricular weight to body weight was significantly higher in MK-TG mice than in WT mice (6.85 ± 0.31 vs. 4.80 ± 0.31, P<0.0001). MK-TG mice had significantly larger left ventricular end-diastolic dimension (3.86 ± 0.23 vs. 3.06 ± 0.19 mm, P<0.05) and lower fractional shortening (19 ± 2 vs. 35 ± 2%, P<0.0001) compared with WT mice. MK-TG mice showed more cardiomyocyte hypertrophy and interstitial fibrosis than WT mice. Consistent with these results, the expression levels of fetal gene and profibrotic gene, such as brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), collagen I, and collagen III, were significantly higher in MK-TG mice than those in WT mice (figure 1). Kaplan-Meyer analysis revealed that the survival rate in MK-TG mice was significantly lower compared with WT mice (figure 2). In the hearts of MK-TG mice, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 after TAC occurred earlier compared with WT mice. These results demonstrated that cardiac overexpression of MK plays a critical role in pressure overload induced cardiac hypertrophy, at least partially via early activation of ERK 1/2.
- © 2011 by American Heart Association, Inc.