Identification and characterization of a dysfunctional cardiac myocyte phenotype: role of bacteria, Toll-like receptors, and endothelin.
Cardiac myocyte dysfunction is clearly identified as underlying the acute heart failure associated with bacterial infection, as well as the chronic syndrome following cardiac damage, but the mechanisms leading to dysfunction in each case are not fully established. It is thought that local hormones such as endothelin 1 (ET-1) can increase the risk of heart failure in acute or chronic conditions. In the current study, we characterize myocytes as populations and identify a novel phenotype of the ventricular cardiac myocyte that does not contract appropriately on electrical stimulation. The noncontractile cardiac myocytes were viable and had normal calcium transients. The proportion of noncontractile cardiac myocytes was increased by bacteria (gram-positive Staphylococcus aureus or gram-negative Escherichia coli). Using selective ligands or myocytes from genetically modified mice, we established that the effects of S. aureus were mediated by Toll-like receptor 2/6 and of E. coli by Toll-like receptor 4. The transition to the noncontractile phenotype was strongly inhibited by ETA antagonism but unaffected by inhibition of NOS, suggesting that ET-1 and not NO mediates this phenomenon. These results are the first to describe the characteristics of this noncontractile phenotype and the mechanisms of its induction by bacteria. Description of the myocyte population, instead of effects only on individual cells, will be more relevant to the prediction of the depression of cardiac function.
Patel
Trupti A
TA
Department of Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Belcher
Elizabeth
E
Warner
Timothy D
TD
Harding
Siân E
SE
Mitchell
Jane A
JA
D000818:Animals; D000077868:Atrasentan; D001419:Bacteria / Q000254:growth & development; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000494:pharmacology; D004926:Escherichia coli / Q000254:growth & development; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013211:Staphylococcus aureus / Q000254:growth & development; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D007545:Isoproterenol; D000077868:Atrasentan