title: Complement Destabilizes Cardiomyocyte Function In Vivo after Polymicrobial Sepsis and In Vitro.
abstract: There is accumulating evidence during sepsis that cardiomyocyte (CM) homeostasis is compromised, resulting in cardiac dysfunction. An important role for complement in these outcomes is now demonstrated. Addition of C5a to electrically paced CMs caused prolonged elevations of intracellular Ca(2+) concentrations during diastole, together with the appearance of spontaneous Ca(2+) transients. In polymicrobial sepsis in mice, we found that three key homeostasis-regulating proteins in CMs were reduced: Na(+)/K(+)-ATPase, which is vital for effective action potentials in CMs, and two intracellular Ca(2+) concentration regulatory proteins, that is, sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and the Na(+)/Ca(2+) exchanger. Sepsis caused reduced mRNA levels and reductions in protein concentrations in CMs for all three proteins. The absence of either C5a receptor mitigated sepsis-induced reductions in the three regulatory proteins. Absence of either C5a receptor (C5aR1 or C5aR2) diminished development of defective systolic and diastolic echocardiographic/Doppler parameters developing in the heart (cardiac output, left ventricular stroke volume, isovolumic relaxation, E' septal annulus, E/E' septal annulus, left ventricular diastolic volume). We also found in CMs from septic mice the presence of defective current densities for Ik1, l-type calcium channel, and Na(+)/Ca(2+) exchanger. These defects were accentuated in the copresence of C5a. These data suggest complement-related mechanisms responsible for development of cardiac dysfunction during sepsis.
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, 89081 Ulm, Germany;
authors: Miriam
authors: 0000-0002-1474-0785
authors: M
authors: Kalbitz
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Fatemeh
authors: F
authors: Fattahi
authors: Division of Cardiovascular Research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Todd J
authors: TJ
authors: Herron
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Jamison J
authors: 0000-0001-6604-6819
authors: JJ
authors: Grailer
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Lawrence
authors: L
authors: Jajou
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Hope
authors: H
authors: Lu
authors: Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm, 89081 Ulm, Germany;
authors: Markus
authors: M
authors: Huber-Lang
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Firas S
authors: FS
authors: Zetoune
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: J Vidya
authors: JV
authors: Sarma
authors: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: Sharlene M
authors: 0000-0001-9802-7188
authors: SM
authors: Day
authors: Department of Pediatric Cardiology, University of Michigan Medical School, Ann Arbor, MI 48109; and Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109.
authors: Mark W
authors: MW
authors: Russell
authors: Division of Cardiovascular Research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors: José
authors: 0000-0003-0080-3500
authors: J
authors: Jalife
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; pward@umich.edu.
authors: Peter A
authors: 0000-0003-1285-8365
authors: PA
authors: Ward
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000276:immunology; D060085:Coinfection / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D015936:Complement C5a / Q000276:immunology; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D051379:Mice; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000276:immunology / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000276:immunology / Q000378:metabolism; D018805:Sepsis / Q000150:complications / Q000276:immunology* / Q000503:physiopathology*
chemical_list: C000591759:C5ar1 protein, mouse; C000594938:C5ar2 protein, mouse; D020746:Calcium Channels, L-Type; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium