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


OBJECTIVE
To define a role for LYCAT in human and murine models of pulmonary fibrosis.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
1 Department of Pharmacology.
Long Shuang
LS
Huang
Biji
B
Mathew
Haiquan
H
Li
Yutong
Y
Zhao
Shwu-Fan
SF
Ma
Imre
I
Noth
Sekhar P
SP
Reddy
Anantha
A
Harijith
Peter V
PV
Usatyuk
Evgeny V
EV
Berdyshev
Naftali
N
Kaminski
Tong
T
Zhou
Wei
W
Zhang
Yanmin
Y
Zhang
Jalees
J
Rehman
Sainath R
SR
Kotha
Travis O
TO
Gurney
Narasimham L
NL
Parinandi
Yves A
YA
Lussier
Joe G N
JG
Garcia
Viswanathan
V
Natarajan
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics*; D000217:Acyltransferases / Q000235:genetics*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002308:Cardiolipins / Q000235:genetics; D015331:Cohort Studies; D004195:Disease Models, Animal; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000175:diagnosis / Q000235:genetics; D017403:In Situ Hybridization; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D011237:Predictive Value of Tests; D011658:Pulmonary Fibrosis / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index
D015415:Biomarkers; D002308:Cardiolipins; D012333:RNA, Messenger; D000217:Acyltransferases; C525544:lysocardiolipin acyltransferase, mouse; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C544777:LCLAT1 protein, human