How Does the Ca(2+)-paradox Injury Induce Contracture in the Heart?-A Combined Study of the Intracellular Ca(2+) Dynamics and Cell Structures in Perfused Rat Hearts.

Abstract

The calcium (Ca(2+))-paradox injury of the heart, induced by restoration of extracellular Ca(2+) after its short-term depletion, is known to provoke cardiomyocyte contracture. However, undetermined is how the Ca(2+)-paradox provokes such a distinctive presentation of myocytes in the heart. To address this, we imaged sequential intracellular Ca(2+) dynamics and concomitant structures of the subepicardial ventricular myocytes in fluo3-loaded, Langendorff-perfused rat hearts produced by the Ca(2+) paradox. Under rapid-scanning confocal microscopy, repletion of Ca(2+) following its depletion produced high-frequency Ca(2+) waves in individual myocytes with asynchronous localized contractions, resulting in contracture within 10 min. Such alterations of myocytes were attenuated by 5-mM NiCl2, but not by verapamil, SEA0400, or combination of ryanodine and thapsigargin, indicating a contribution of non-specific transmembrane Ca(2+) influx in the injury. However, saponin-induced membrane permeabilization of Ca(2+) showed no apparent contracture despite the emergence of high-frequency Ca(2+) waves, indicating an essential role of myocyte-myocyte and myocyte-extracellular matrix (ECM) mechanical connections in the Ca(2+) paradox. In immunohistochemistry Ca(2+) depletion produced separation of the intercalated disc that expresses cadherin and dissipation of β-dystroglycan located along the sarcolemma. Taken together, along with the trans-sarcolemmal Ca(2+) influx, disruption of cell-cell and cell-ECM connections is essential for contracture in the Ca(2+)-paradox injury.

• Authors: Hiroki Mani, Hideo Tanaka, Tetsuya Adachi, Masaya Ikegawa, Ping Dai, Naohisa Fujita, Tetsuro Takamatsu
• Journal: Acta histochemica et cytochemica (Acta Histochem Cytochem) Vol. 48 Issue 1 Pg. 1-8 ( 2015) ISSN: 0044-5991 [Print] Japan
• PMID: 25861132 (Publication Type: Journal Article)