Abstract 1282: β1 Integrins Play a Critical Role in β-Adrenergic Receptor-Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling
Background: Sympathetic nerve activity increases in the heart during heart failure. We hypothesized that β1 integrins play a protective role in chronic β-adrenergic receptor (β-AR) stimulated cardiac myocyte apoptosis and heart failure.
Methods and Results: L-isoproterenol (iso; 400 μg/kg/h) was infused in a group of wild-type (WT) and β1 integrin heterozygous knockout (hKO) mice. Alterations in LV structure and function, cardiac myocyte apoptosis and activity of signaling molecules was assessed following 7 and 30 days of iso-infusion. Iso-infusion increased heart weight-to-body weight (HW/BW) ratios in both groups. However, the increase was significantly higher in WT-iso. M-mode echocardiographic measurements demonstrated increased percent fractional shortening (%FS) in WT-iso following 7 and 30 days of iso-infusion. Interestingly, %FS was significantly reduced in hKO-iso group following 30 days of iso-infusion. Peak LV developed pressure (LVDP) and LV end diastolic pressure (LVEDP) measured using Langendorff-perfusion analyses were significantly increased in WT-iso when compared to sham and hKO-iso groups (P<0.05 vs WT-sham and hKO-Iso). The number of apoptotic myocytes was significantly higher in hKO-iso hearts when compared to WT-iso at 7 and 30 days following iso-infusion (p<0.001 WT-iso vs hKO-iso). Myocyte cross sectional area and fibrosis were increased in both iso groups when compared to their respective shams. However, the increase in fibrosis was significantly lower in hKO-iso hearts (P<0.05 vs WT-iso). Western blot analysis indicated increased phosphorylation of JNK and ERK1/2 and protein expression of GRP78 following 7 days of iso-infusion. Interestingly, the increase in p-JNK was significantly higher in hKO-iso when compared to WT-iso group (P<0.01 vs WT-iso; n=4). Iso-infusion significantly increased the level of MMP-2 in hKO-iso hearts, whereas MMP-9 was significantly increased in WT-iso group.
Conclusion: β1 integrins play a crucial role in β-AR-stimulated apoptosis with effects on left ventricular structure and function.