Different roles for contracture and calpain in calcium paradox-induced heart injury.

Abstract

The Ca(2+) paradox represents a good model to study Ca(2+) overload injury in ischemic heart diseases. We and others have demonstrated that contracture and calpain are involved in the Ca(2+) paradox-induced injury. This study aimed to elucidate their roles in this model. The Ca(2+) paradox was elicited by perfusing isolated rat hearts with Ca(2+)-free KH media for 3 min or 5 min followed by 30 min of Ca(2+) repletion. The LVDP was measured to reflect contractile function, and the LVEDP was measured to indicate contracture. TTC staining and the quantification of LDH release were used to define cell death. Calpain activity and troponin I release were measured after Ca(2+) repletion. Ca(2+) repletion of the once 3-min Ca(2+) depleted hearts resulted in almost no viable tissues and the disappearance of contractile function. Compared to the effects of the calpain inhibitor MDL28170, KB-R7943, an inhibitor of the Na(+)/Ca(2+) exchanger, reduced the LVEDP level to a greater extent, which was well correlated with improved contractile function recovery and tissue survival. The depletion of Ca(2+) for 5 min had the same effects on injury as the 3-min Ca(2+) depletion, except that the LVEDP in the 5-min Ca(2+) depletion group was lower than the level in the 3-min Ca(2+) depletion group. KB-R7943 failed to reduce the level of LVEDP, with no improvement in the LVDP recovery in the hearts subjected to the 5-min Ca(2+) depletion treatment; however, KB-R7943 preserved its protective effects in surviving tissue. Both KB-R7943 and MDL28170 attenuated the Ca(2+) repletion-induced increase in calpain activity in 3 min or 5 min Ca(2+) depleted hearts. However, only KB-R7943 reduced the release of troponin I from the Ca(2+) paradoxic heart. These results provide evidence suggesting that contracture is the main cause for contractile dysfunction, while activation of calpain mediates cell death in the Ca(2+) paradox.

• Authors: Jian-Ying Zhang, Wei Tong, Feng Wu, Sheng-Hui Bi, Ming Xu, Zhen-Xiao Jin, Yang Yang, Xiao-Fan Jiang, Jing-Jun Zhou
• Journal: PloS one (PLoS One) Vol. 7 Issue 12 Pg. e52270 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23284963 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
• Dipeptides
• Sodium-Calcium Exchanger
• Calpain
• Thiourea
• Calcium
• calpain inhibitor III

Topics

• Animals
• Blotting, Western
• Calcium (metabolism)
• Calpain (antagonists & inhibitors, metabolism)
• Contracture (physiopathology)
• Dipeptides (pharmacology)
• Heart Injuries (metabolism, physiopathology)
• Male
• Myocardial Infarction
• Myocardial Reperfusion Injury
• Rats
• Rats, Sprague-Dawley
• Sodium-Calcium Exchanger (antagonists & inhibitors, metabolism)
• Thiourea (analogs & derivatives, pharmacology)