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This Article Full Text Full Text (PDF) All Versions of this Article: 287/3/H1013    most recent 01177.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Davani, E. Y. Articles by Walley, K. R. Search for Related Content PubMed PubMed Citation Articles by Davani, E. Y. Articles by Walley, K. R.

Novel regulatory mechanism of cardiomyocyte contractility involving ICAM-1 and the cytoskeleton

Critical Care Research Laboratories, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6Z 1Y6

Submitted 16 December 2003 ; accepted in final form 8 April 2004

ICAM-1 mediates interaction of cardiomyocytes with the extracellular matrix and leukocytes and may play a role in altering contractility. To investigate this possibility, rat ventricular cardiomyocytes were activated using TNF-, IL-1, or LPS, washed, cultured with quiescent rat polymorphonuclear leukocytes (PMNs) for 4 h, and electrically stimulated to determine fractional shortening. PMNs cultured with activated cardiomyocytes reduced control fractional shortening of 20.5 ± 0.7% by –2.8 ± 0.3% per adherent PMN (P < 0.001). Fixing PMNs with paraformaldehyde or glutaraldehyde did not prevent PMN-mediated decreases in cardiomyocyte fractional shortening. However, PMN adherence and decreased fractional shortening were prevented by anti-ICAM-1 and anti-CD18 antibodies. Reduced fractional shortening was reproduced in the absence of PMNs by ICAM-1 binding using cross-linking antibodies (reduced by 36 ± 3% from control, P < 0.01). Immunofluorescent staining demonstrated increased cortical cytoskeleton-associated focal adhesion kinase expression after ICAM-1 cross-linking, suggesting involvement of the actin cytoskeleton. Indeed, disruption of F-actin filament assembly using cytochalasin D or latrunculin A did not prevent PMN adherence but prevented decreased fractional shortening. Inhibition of the cytoskeleton-associated Rho-kinase pathway with HA-1077 prevented ICAM-1-mediated decreases in cardiomyocyte contractility, further suggesting a central role of the actin cytoskeleton. Importantly, ICAM-1 cross-linking did not alter the total intracellular Ca²⁺ transient during cardiomyocyte contraction but greatly increased heterogeneity of intracellular Ca²⁺ release. Thus we have identified a novel regulatory mechanism of cardiomyocyte contractility involving the actin cytoskeleton as a central regulator of the normally highly coordinated pattern of sarcoplasmic Ca²⁺ release. Cardiomyocyte ICAM-1 binding, by PMNs or other ligands, induces decreased cardiomyocyte contractility via this pathway.

intracellular signaling; focal adhesion kinase; Rho; calcium

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