title: 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: Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Graduate School of Medical Science ; Department of Molecular Genetics and Laboratory Medicine, Kyoto Prefectural University of Medicine, Graduate School of Medical Science.
authors: Hiroki
authors: H
authors: Mani
authors: Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Graduate School of Medical Science.
authors: Hideo
authors: H
authors: Tanaka
authors: Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Graduate School of Medical Science.
authors: Tetsuya
authors: T
authors: Adachi
authors: Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Graduate School of Medical Science , Kyoto 602-8566, Japan.
authors: Masaya
authors: M
authors: Ikegawa
authors: Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Graduate School of Medical Science.
authors: Ping
authors: P
authors: Dai
authors: Department of Molecular Genetics and Laboratory Medicine, Kyoto Prefectural University of Medicine, Graduate School of Medical Science.
authors: Naohisa
authors: N
authors: Fujita
authors: Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Graduate School of Medical Science.
authors: Tetsuro
authors: T
authors: Takamatsu
keywords: Ca2+ paradox; Ca2+ wave; contracture; heart; β-dystroglycan