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2015 ; 108
(2
): 232-42
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Citrullination of myofilament proteins in heart failure
#MMPMID26113265
Fert-Bober J
; Giles JT
; Holewinski RJ
; Kirk JA
; Uhrigshardt H
; Crowgey EL
; Andrade F
; Bingham CO 3rd
; Park JK
; Halushka MK
; Kass DA
; Bathon JM
; Van Eyk JE
Cardiovasc Res
2015[Nov]; 108
(2
): 232-42
PMID26113265
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AIMS: Citrullination, the post-translational conversion of arginine to citrulline
by the enzyme family of peptidylarginine deiminases (PADs), is associated with
several diseases, and specific citrullinated proteins have been shown to alter
function while others act as auto-antigens. In this study, we identified
citrullinated proteins in human myocardial samples, from healthy and heart
failure patients, and determined several potential functional consequences.
Further we investigated PAD isoform cell-specific expression in the heart.
METHODS AND RESULTS: A citrullination-targeted proteomic strategy using
data-independent (SWATH) acquisition method was used to identify the modified
cardiac proteins. Citrullinated-induced sarcomeric proteins were validated using
two-dimensional gel electrophoresis and investigated using biochemical and
functional assays. Myocardial PAD isoforms were confirmed by RT-PCR with PAD2
being the major isoform in myocytes. In total, 304 citrullinated sites were
identified that map to 145 proteins among the three study groups: normal,
ischaemia, and dilated cardiomyopathy. Citrullination of myosin (using HMM
fragment) decreased its intrinsic ATPase activity and inhibited the
acto-HMM-ATPase activity. Citrullinated TM resulted in stronger F-actin binding
and inhibited the acto-HMM-ATPase activity. Citrullinated TnI did not alter the
binding to F-actin or acto-HMM-ATPase activity. Overall, citrullination of
sarcomeric proteins caused a decrease in Ca(2+) sensitivity in skinned
cardiomyocytes, with no change in maximal calcium-activated force or hill
coefficient. CONCLUSION: Citrullination unique to the cardiac proteome was
identified. Our data indicate important structural and functional alterations to
the cardiac sarcomere and the contribution of protein citrullination to this
process.
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