Abstract 9407: Overexpression of R120g αβ -Crystallin Causes Cardiac Arrhythmias, Reduced Heart Rate Variability, Alteration in the Expression Of Ca2+ Handling Proteins and Er Stress in Mice
Upregulation of αβ-crystallin (Cryαβ), a small heat shock protein, is associated with a variety of diseases, including desmin-related myopathies. Cryαβ, which binds to both desmin and cytoplasmic actin, may participate as a chaperone in intermediate filament formation and maintenance, and Cryαβ is abundant in cardiac and skeletal muscle. A mutation from arginine at the 120 amino acid residue to glycine (R120G) of Cryαβ has been linked to a familial desminopathy. Mice with cardiac specific overexpression of the R120G mutation in Cryαβ (CryαβR120G) have been known to suddenly die at 6-7 months without any obvious symptoms of heart failure. Therefoe, we investigated the cause of death in CryαβR120G transgenic mice. We prepared protein samples from the left ventricular tissues of the young and old mice (Young: 10 weeks, Old: 28 weeks), and examined a change in Ca2+ handling proteins. We found that the expression levels of SERCA2 and other Ca2+ handling proteins including phospholamban, ryanodine receptor 2, and calsequestrin 2 were significantly decreased in old CryαβR120G transgenic mice. Old CryαβR120G transgenic mice exhibited lower heart rate variability (HRV) such as heart rate, total power, and low frequency. In addition, continuous ECG monitoring uncovered that overexpression of CryαβR120G causesd cardiac arrhythmias such as ventricular tachycardia, atrioventricular block, and atrial flutter. We also found that the expression levels of endoplasmic reticulum (ER) degradation enhancing, α-mannosidase-like protein, inositol requirement 1, and x-box binding protein 1 mRNAs were significantly increased in old CryαβR120G transgenic mice, indicating that CryαβR120G transgenic mice exhibited ER stress. Thus the present study demonstrated that CryαβR120G lead to various arrhythmias, decreased autonomous tone, impaired Ca2+ regulation via the sarcoplasmic reticulum and enhanced ER stress with a concomitant decrease in lifespan.
- © 2011 by American Heart Association, Inc.