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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/H1490    most recent 00910.2007v1 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 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 Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Tzeng, H.-P. Articles by Mann, D. L. Search for Related Content PubMed PubMed Citation Articles by Tzeng, H.-P. Articles by Mann, D. L.

Negative inotropic effects of high-mobility group box 1 protein in isolated contracting cardiac myocytes

¹Department of Medicine, Winters Center for Heart Failure Research; ²Texas Heart Institute at Saint Luke's Episcopal Hospital; ³Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas; ⁴Molecular and Cellular Cardiology Laboratories, Cardiovascular Research Group, Temple University School of Medicine, Philadelphia, Pennsylvania

Submitted 6 August 2007 ; accepted in final form 23 January 2008

High-mobility group box 1 (HMGB1) released from necrotic cells or macrophages functions as a late inflammatory mediator and has been shown to induce cardiovascular collapse during sepsis. Thus far, however, the effect(s) of HMGB1 in the heart are not known. We determined the effects of HMGB1 on isolated feline cardiac myocytes by measuring sarcomere shortening in contracting cardiac myocytes, intracellular Ca²⁺ transients by using fluo-3, and L-type calcium currents by using whole cell perforate configuration of the patch-clamp technique. Treatment of isolated myocytes with HMGB1 (100 ng/ml) resulted in a 70% decrease in sarcomere shortening and a 50% decrease in the height of the peak Ca²⁺ transient within 5 min (P < 0.01). The immediate negative inotropic effects of HMGB1 on cell contractility and calcium homeostasis were partially reversible upon washout of HMGB1. A significant inhibition of the inward L-type calcium currents was also documented by the patch-clamp technique. HMGB1 induced the PKC- translocation, and a PKC inhibitor significantly attenuated the negative inotropic effects of HMGB1. These studies show for the first time that HMGB1 impairs sarcomere shortening by decreasing calcium availability in cardiac myocytes through modulating membrane calcium influx and suggest that HMGB1 maybe acts as a novel myocardial depressant factor during cardiac injury.

inflammation; innate immunity; myocardial function; sepsis

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