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

Abstract

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-alpha, IL-1beta, 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.

T Cells Are Essential for Bacterial Clearance, and Gamma Interferon, Tumor Necrosis Factor Alpha, and B Cells Are Crucial for Disease Development inCoxiella burnetiiInfection in Mice

“…TNF-␣ Ϫ/Ϫ mice infected with NM I had the most severe heart lesions. TNF-␣ is known to upregulate expression of adhesion receptors, including intercellular adhesion molecule 1 in cardiomyocytes and V-and P-selectin and vascular cell adhesion molecule 1 in endothelial cells that mediate efficient binding of circulating leukocytes (10,14). We speculate that the severe lesions found in TNF-␣ Ϫ/Ϫ mice were due to the combination of bacteremia and a lack of efficient leukocyte recruitment.…”

Inflammation in Myocardial Diseases

“…63,66,71,76,78 -80 , and finally produce 2 small calcium regulated molecules (S100A8 and S100A9) that suppress calcium flux via the RAGE receptor (Table 2). 81 This cardiomyocyteinflammatory response involving cytokines, 82 chemokines and the subsequently recruited leukocytes, 57,63 and cellsurface-adhesion molecules 63,66 leads to decreased cardiomyocyte contractility, thereby modulating peak systolic stress and strain and conceivably impairing the repair processes. It appears that some members of the TLR family of innate immune mediate recognition of local danger signals and initiate an inflammatory response.…”

Acute inhibition of Rho-kinase improves cardiac contractile function in streptozotocin-diabetic rats

“…A number of studies have implicated a role for the cytoskeleton in conditions of impaired cardiac performance [35]. For instance, increased actin polymerization in cardiomyocytes has been associated with decreased contractility due to disruption of intracellular Ca 2+ release [36]. Furthermore, RhoA-induced increases in actin polymerization can promote the exocytosis of lipoprotein lipase and increase fatty acid metabolism [37], which is associated with impaired cardiac function and lipotoxicity in chronic diabetes [38].…”