title: Pivotal role of phospholipase D1 in tumor necrosis factor-α-mediated inflammation and scar formation after myocardial ischemia and reperfusion in mice.
abstract: Myocardial inflammation is critical for ventricular remodeling after ischemia. Phospholipid mediators play an important role in inflammatory processes. In the plasma membrane they are degraded by phospholipase D1 (PLD1). PLD1 was shown to be critically involved in ischemic cardiovascular events. Moreover, PLD1 is coupled to tumor necrosis factor-α signaling and inflammatory processes. However, the impact of PLD1 in inflammatory cardiovascular disease remains elusive. Here, we analyzed the impact of PLD1 in tumor necrosis factor-α-mediated activation of monocytes after myocardial ischemia and reperfusion using a mouse model of myocardial infarction. PLD1 expression was highly up-regulated in the myocardium after ischemia/reperfusion. Genetic ablation of PLD1 led to defective cell adhesion and migration of inflammatory cells into the infarct border zone 24 hours after ischemia/reperfusion injury, likely owing to reduced tumor necrosis factor-α expression and release, followed by impaired nuclear factor-κB activation and interleukin-1 release. Moreover, PLD1 was found to be important for transforming growth factor-β secretion and smooth muscle α-actin expression of cardiac fibroblasts because myofibroblast differentiation and interstitial collagen deposition were altered in Pld1(-/-) mice. Consequently, infarct size was increased and left ventricular function was impaired 28 days after myocardial infarction in Pld1(-/-) mice. Our results indicate that PLD1 is crucial for tumor necrosis factor-α-mediated inflammation and transforming growth factor-β-mediated collagen scar formation, thereby augmenting cardiac left ventricular function after ischemia/reperfusion.
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University Clinic of Tuebingen, Tuebingen, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schönberger
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University Clinic of Tuebingen, Tuebingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Jürgens
authors.affiliation: Institutes of Pharmacology and Clinical Pharmacology, University Clinic of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Müller
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University Clinic of Tuebingen, Tuebingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Armbruster
authors.affiliation: Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, University Clinic of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Niermann
authors.affiliation: Institutes of Pharmacology and Clinical Pharmacology, University Clinic of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Gorressen
authors.affiliation: Institutes of Biochemistry and Molecular Biology II, University Clinic of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Sommer
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York.
authors.forename: Huasong
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York.
authors.forename: Gilbert
authors.initials: G
authors.lastname: di Paolo
authors.affiliation: Institutes of Biochemistry and Molecular Biology II, University Clinic of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Institutes of Pharmacology and Clinical Pharmacology, University Clinic of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University Clinic of Tuebingen, Tuebingen, Germany.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University Clinic of Tuebingen, Tuebingen, Germany; Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, University Clinic of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. Electronic address: margitta.elvers@med.uni-duesseldorf.de.
authors.forename: Margitta
authors.initials: M
authors.lastname: Elvers
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D010739:Phospholipase D / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D010739:Phospholipase D; C106801:phospholipase D1