Abstract 12501: Integrin Overexpression Improves Survival Rate After Myocardial Infarction Through Attenuation of ER Stress
Introduction: Alterations in calcium homeostasis in the endoplasmic/sarcoplasmic reticulum (ER) can cause stress that ultimately may affect ventricular function. Previously, we reported that α7β1D integrin modified Ca2+ regulatory pathways in the cardiomyocyte via ryanodine receptor 2 (RyR2) stabilization, and offers a means to protect the myocardium from ischemia/reperfusion injury. In the present study, we hypothesized that integrin overexpression (OE) would have beneficial effects against post-myocardial infarction (MI) left ventricular (LV) remodeling via the inhibition of ER stress.
Methods: MI was created in 9-12 week old α7β1D integrin overexpressing male mice and age/gender-matched littermate controls by left coronary artery ligation. Groups were followed for 4 weeks post-MI.
Results: Survival rate was significantly increased in α7β1D integrin OE mice (90% vs. control, 38.5%, p<0.05). There was no significant difference in LV fractional shortening between both groups (Control 8.7±0.4%, α7β1D 15.8±3.2%, p=0.07). LV hypertrophy was decreased in α7β1D integrin OE mice (674±23 um2 vs. control, 814±12 um2 p<0.05). Real-time reverse transcriptase PCR showed that the hypertrophic markers, ANF, BNP, α-skeletal actin and β-myosin heavy chain were significantly decreased in the α7β1D OE mice vs. control. Ca2+ transport proteins including sarcoplasmic reticulum Ca2+-ATPase (SERCA), RyR2, sodium-calcium exchanger (NCX1), Ca2+ storage protein calreticulin (CRT), and phospholamban were evaluated by Western blot analysis. Cellular levels of the ER stress marker, phosphorylated eukaryotic initiation factor 2a (eIF2a-P), were also examined. Integrin α7β1D OE did not alter expression of Ca2+ transport proteins (SERCA2a, NCX-1 or RyR2) but did reduce RyR2 phosphorylation at serine 2808. eIF2a-P and CRT were significantly decreased in α7β1D integrin OE mice. These results suggest that α7β1D integrin OE decreases ER stress in the post-infarct failing heart.
Conclusion: Integrin α7β1D OE improved survival rate of postmyocardial infarction and does so at least in part through attenuation of ER stress. These findings imply that modulation of myocyte integrin function may be a new protective strategy useful in MI.
Author Disclosures: H. Okada: None. G. Takemura: None. N. Lai: None. A.M. Manso: None. T. Watanabe: None. K. Morishita: None. S. Ogura: None. S. Minatoguchi: None. R.S. Ross: None.
- © 2014 by American Heart Association, Inc.