Author + information
- Yu Juan
Myocardial ischemia and reperfusion injury(MIRI) is a serious disease which threats human health and life. Recent studies reports Na+/Ca2+/Calmodulin-dependent protein kinase II (CaMII) feedback plays vital role in heart failure. However, the role of CaMKII/[Na+]i/[Ca2+]i feedback in MIRI is still unclear.
To ensure the influence of INa and CaMKII on MIRI, we used Roberts-Christini MIRI AP model, which combined the dynamic changes of intracellular pH (pHi), extracellular pH(pHe), 13 ion currents and 6 pump exchangers. All simulations were run using a pacing rate of 1 Hz. Four groups were set as: Control(MIRI only), INa 50% block, CaMKII 50% block and both(INa 50% and CaMKII 50% block),respectively.
During ischemia stage, pHi and pHe were reduced to 5.8 and 6.2 from pre-ischemia stage(pHe 7.4,pHi 7.2), respectively. AP amplitude was also decreased. Sodium overload existed in 10-minutes ischemia stage, compared with pre-ischemia, exacerbating in 10-minutes reperfusion stage. INa 50% block slightly reduced intracellular sodium concertration([Na]i), while CaMKII 50% block and both block groups reduced [Na]i more significantly. Calcium overload were found in control and INa 50% block, while it was reduced significantly in CaMKII 50% block and both block, which reveals that CaMKII is essential to keep calcium overload, not INa. Consistently, we found NCX current were also reduced in CaMKII 50% block and both block,which suggested that NCX played downstream role of CaMKII and calcium overload.
To further explore the mechanisms of CaMKII and INa on MIRI, we analyzed various currents which might be related with sodium and calcium overload. During pre-ischemia stage, we can see that Peak INa keeps in 350uA/uF in normal, while it reduced half(175uA/uF) in INa 50% block and both groups. All other currents, such as calcium-sodium exchanger (ICaNa), INaL, background sodium current (INab), sodium-potassium exchanger (INaK), ATP-inactivated potassium current (IKatp), sodium-calcium exchanger (INCX), sodium-bicarbonate symporter (INBC), sodium-exchanger(INHE), are nearly the same values in these four groups. During 10-minutes ischemia stage, Peak INa among the four groups were reduced significantly(40-60uA/uF). Peak INab increased in CaMKII 50% block and both INa-CaMKII block groups, while all other currents kept the similar values among four groups. During 10-minutes of reperfusion stage, Peak ICaNa were significantly increased in CaMKII 50% block and both INa-CaMKII block groups, which reveals ICaNa takes responsibility for reducing calcium overload in MIRI.
Our study indicate that CaMKII plays a key role in calcium overload in MIRI, not INa, blocking of CaMKII activated INCX and ICaNa currents, transferred more Ca2+ to the outside of cell, subsequently reducing calcium overload, and finally alleviated MIRI. Inhibited activation of CaMKII might be a potential treatment on MIRI.