The mitochondrial cardiolipin remodeling enzyme lysocardiolipin acyltransferase is a novel target in pulmonary fibrosis.

TitleThe mitochondrial cardiolipin remodeling enzyme lysocardiolipin acyltransferase is a novel target in pulmonary fibrosis.
Publication TypeJournal Article
Year of Publication2014
AuthorsHuang LShuang, Mathew B, Li H, Zhao Y, Ma S-F, Noth I, Reddy SP, Harijith A, Usatyuk PV, Berdyshev EV, Kaminski N, Zhou T, Zhang W, Zhang Y, Rehman J, Kotha SR, Gurney TO, Parinandi NL, Lussier YA, Garcia JGN, Natarajan V
JournalAm J Respir Crit Care Med
Volume189
Issue11
Pagination1402-15
Date Published2014 Jun 01
ISSN Number1535-4970
Keywords1-Acylglycerol-3-Phosphate O-Acyltransferase, Acyltransferases, Animals, Biomarkers, Cardiolipins, Cohort Studies, Disease Models, Animal, Humans, Idiopathic Pulmonary Fibrosis, In Situ Hybridization, Leukocytes, Mononuclear, Mice, Mitochondria, Predictive Value of Tests, Pulmonary Fibrosis, RNA, Messenger, Sensitivity and Specificity, Severity of Illness Index
Abstract

<p><b>RATIONALE: </b>Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis.</p><p><b>OBJECTIVES: </b>To define a role for LYCAT in human and murine models of pulmonary fibrosis.</p><p><b>METHODS: </b>We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge.</p><p><b>MEASUREMENTS AND MAIN RESULTS: </b>LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection.</p><p><b>CONCLUSIONS: </b>This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis.</p>

DOI10.1164/rccm.201310-1917OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID24779708
PubMed Central IDPMC4098083
Grant ListP01 HL98050 / HL / NHLBI NIH HHS / United States
RC2 HL101740 / HL / NHLBI NIH HHS / United States
U01 HL108642 / HL / NHLBI NIH HHS / United States
HL101740 / HL / NHLBI NIH HHS / United States
R01 GM094220 / GM / NIGMS NIH HHS / United States
R01-GM094220 / GM / NIGMS NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States
HL099619 / HL / NHLBI NIH HHS / United States
RC1 HL099619 / HL / NHLBI NIH HHS / United States