Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by particulate matter (PM) isolated from ambient air and linked to prolonged repolarization and cardiac arrhythmia. We evaluated whether alpha B-crystallin (CryAB), a heat shock protein, could prevent the arrhythmogenic effects of PM by preventing CaMKII activation. CryAB was delivered into cardiac cells using a TAT-protein transduction domain (TAT-CryAB). ECGs were measured before and after tracheal exposure of diesel exhaust particles (DEP) and each intervention in adult Sprague-Dawley rats. After endotracheal exposure of DEP (200μg/mL for 30minutes, n=11), QT intervals were prolonged from 115±14ms to 144±20ms (p=0.03), and premature ventricular contractions were observed more frequently (0% vs. 44%) than control (n=5) and TAT-Cry (n=5). However, DEP-induced arrhythmia was not observed in TAT-CryAB (1mg/kg) pretreated rats (n=5). In optical mapping of Langendorff-perfused rat heats, compared with baseline, DEP infusion of 12.5μg/mL (n=12) increased apicobasal action potential duration (APD) differences from 2±6ms to 36±15ms (p<0.001), APD restitution slope from 0.26±0.07 to 1.19±0.11 (p<0.001) and ventricular tachycardia (VT) from 0% to 75% (p<0.001). DEP infusion easily induced spatially discordant alternans. However, the effects of DEP were prevented by TAT-CryAB (1mg/kg, n=9). In rat myocytes, while DEP increased reactive oxygen species (ROS) generation and phosphated CaMKII, TAT-CryAB prevented these effects. In conclusion, CryAB, a small heat shock protein, might prevent the arrhythmogenic effects of PM by attenuating ROS generation and CaMKII activation.
Bibliographical noteFunding Information:
This study was supported in part by research grants from Yonsei University College of Medicine ( 8-2011-0250 , 7-2011-0758 , 7-2011-0702 , 7-2011-0015 ), the Basic Science and National Research Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science and Technology ( 20120007604 , 2012045367 ), and a grant from the Korea Health 21 R&D Project , Ministry of Health and Welfare, Republic of Korea ( A120478 ). Appendix A
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