Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury.

Autor:	Chun N; Nephrology Division, Department of Medicine and Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America., Haddadin AS; Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America., Liu J; Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America., Hou Y; Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America., Wong KA; Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America., Lee D; Department of Surgery, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America., Rushbrook JI; Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America., Gulaya K; Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America., Hines R; Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America., Hollis T; Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America., Nistal Nuno B; Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, United States of America., Mangi AA; Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America., Hashim S; Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America., Pekna M; Department of Medical Chemistry and Cell Biology, Göteborg University, Göteborg, Sweden., Catalfamo A; Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America., Chin HY; Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America., Patel F; Department of Biomedical Sciences, Long Island University, Brookville, New York, United States of America., Rayala S; Department of Biomedical Sciences, Long Island University, Brookville, New York, United States of America., Shevde K; Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America., Heeger PS; Nephrology Division, Department of Medicine and Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America., Zhang M; Department of Anesthesiology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America.; Department of Cell Biology, College of Medicine, SUNY Downstate Medical Center, Brooklyn, New York, United States of America.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2017 Jun 29; Vol. 12 (6), pp. e0179450. Date of Electronic Publication: 2017 Jun 29 (Print Publication: 2017).
DOI:	10.1371/journal.pone.0179450
Abstrakt:	The pathophysiology of myocardial injury that results from cardiac ischemia and reperfusion (I/R) is incompletely understood. Experimental evidence from murine models indicates that innate immune mechanisms including complement activation via the classical and lectin pathways are crucial. Whether factor B (fB), a component of the alternative complement pathway required for amplification of complement cascade activation, participates in the pathophysiology of myocardial I/R injury has not been addressed. We induced regional myocardial I/R injury by transient coronary ligation in WT C57BL/6 mice, a manipulation that resulted in marked myocardial necrosis associated with activation of fB protein and myocardial deposition of C3 activation products. In contrast, in fB-/- mice, the same procedure resulted in significantly reduced myocardial necrosis (% ventricular tissue necrotic; fB-/- mice, 20 ± 4%; WT mice, 45 ± 3%; P < 0.05) and diminished deposition of C3 activation products in the myocardial tissue (fB-/- mice, 0 ± 0%; WT mice, 31 ± 6%; P<0.05). Reconstitution of fB-/- mice with WT serum followed by cardiac I/R restored the myocardial necrosis and activated C3 deposition in the myocardium. In translational human studies we measured levels of activated fB (Bb) in intracoronary blood samples obtained during cardio-pulmonary bypass surgery before and after aortic cross clamping (AXCL), during which global heart ischemia was induced. Intracoronary Bb increased immediately after AXCL, and the levels were directly correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis (Spearman coefficient = 0.465, P < 0.01). Taken together, our results support the conclusion that circulating fB is a crucial pathophysiological amplifier of I/R-induced, complement-dependent myocardial necrosis and identify fB as a potential therapeutic target for prevention of human myocardial I/R injury.
Databáze:	MEDLINE
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