Abstract 2657: The Increased Local Insulin-like Growth Factor-1 To IGF Binding Protein-3 Ratio In The Pathogenesis Of The Left Ventricular Hypertrophy In Humans: Augmentation By Matrix Metalloproteinase-2 Activity
Insulin-like growth factor (IGF)-1 is a potent mitogen and is said to enhance ventricular hypertrophy. IGF-1 is present as an IGF-1-IGF binding protein-3 (IGFBP-3) complex, and its free form shows bioactivity. Recently, the matrix metalloproteinases (MMPs) were shown to facilitate IGF-1 bioactibity through the degradation of IGFBP-3. To clarify the relation of IGF-1 and IGFBP-3 to MMPs and their roles in human cardiac hypertrophy, we measured levels of total IGF-1, IGFBP-3, MMP-2, and MMP-9 in the pericardial fluid, which reflects the myocardial interstitial fluid, obtained from 51 patients with aortic valvular disease (AVD) (n=36) (aortic stenosis (n=24), aortic regurgitation (n=12)) and mitral valvular disease (MVD) (n=15) (mitral stenosis (n=6), mitral regurgitation (n=9)) who underwent open heart surgery. Levels of total IGF-1 and IGFBP-3 were measured by enzyme immunoassay, and the activities of MMP-2 and MMP-9 by gelatin zymography. Left ventricular mass index (LVMI) was estimated by echocardiography. Pericardial total IGF-1 level (ng/ml) in AVD (32±19) was higher than that in MVD (20±17) (p<0.05). Pericardial IGFBP-3 level (ng/ml) was not different between AVD (715±318) and MVD (857±441). When total IGF-1/IGFBP-3 ratio, indicative of potency of IGF-1 action, was estimated in each patient, it was significantly higher in AVD than in MVD (p<0.017). There was no difference in MMP-9 activity between AVD and MVD, while MMP-2 activity in AVD was higher than that in MVD (p<0.05). LVMI in AVD was significantly greater than in MVD (p<0.05). In the linear regression analysis for all patients, pericardial total IGF-1/IGFBP-3 ratio was positively correlated with LVMI (r=0.3, p<0.05). To further clarify the relationship among total IGF-1, IGFBP-3 and MMP-2, we examined the effect of IGF-1 on smooth muscle cell (SMC) proliferation. IGF-1 (250 ng/ml) induced SMC proliferation, and this was inhibited by IGFBP-3 (2500 ng/ml). This inhibiting effect of IGFBP-3 was reversed by co-treatment with MMP-2 (0.005 unit). These findings suggest that cardiac IGF-1/IGFBP-3 system, which is augmented by MMP-2, plays an important role in the pathogenesis of LV hypertrophy.