The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

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...

Full description

Saved in:
Bibliographic Details
Published in:American journal of respiratory and critical care medicine 2014-06, Vol.189 (11), p.1402-1415
Main Authors: LONG SHUANG HUANG, MATHEW, Biji, KAMINSKI, Naftali, TONG ZHOU, WEI ZHANG, YANMIN ZHANG, REHMAN, Jalees, KOTHA, Sainath R, GURNEY, Travis O, PARINANDI, Narasimham L, LUSSIER, Yves A, GARCIA, Joe G. N, HAIQUAN LI, NATARAJAN, Viswanathan, YUTONG ZHAO, MA, Shwu-Fan, NOTH, Imre, REDDY, Sekhar P, HARIJITH, Anantha, USATYUK, Peter V, BERDYSHEV, Evgeny V
Format: Article
Language:English
Subjects:
1-Acylglycerol-3-Phosphate O-Acyltransferase - genetics
Acyltransferases - genetics
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Apoptosis
Biological and medical sciences
Biomarkers - metabolism
Carbon monoxide
Cardiolipins - genetics
Cohort Studies
Disease Models, Animal
Enzymes
Fibroblasts
Genes
Genomes
Genomics
Humans
Idiopathic Pulmonary Fibrosis - diagnosis
Idiopathic Pulmonary Fibrosis - genetics
In Situ Hybridization
Intensive care medicine
Leukocytes, Mononuclear - metabolism
Medical prognosis
Medical sciences
Mice
Mitochondria - genetics
Mitochondria - metabolism
Original
Patients
Pneumology
Predictive Value of Tests
Pulmonary fibrosis
Pulmonary Fibrosis - diagnosis
Pulmonary Fibrosis - enzymology
Pulmonary Fibrosis - genetics
Radiation
Respiratory system : syndromes and miscellaneous diseases
RNA, Messenger - metabolism
Sensitivity and Specificity
Severity of Illness Index
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. To define a role for LYCAT in human and murine models of pulmonary fibrosis. 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. 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. 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.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201310-1917OC