Mkk4 is a negative regulator of the transforming growth factor beta 1 signaling associated with atrial remodeling and arrhythmogenesis with age.
BACKGROUND
Atrial fibrillation (AF), often associated with structural, fibrotic change in cardiac tissues involving regulatory signaling mediators, becomes increasingly common with age. In the present study, we explored the role of mitogen-activated protein kinase kinase 4 (Mkk4), a critical component of the stress-activated mitogen-activated protein kinase family, in age-associated AF.


RESULTS
We developed a novel mouse model with a selective inactivation of atrial cardiomyocyte Mkk4 (Mkk4(ACKO)). We characterized and compared electrophysiological, histological, and molecular features of young (3- to 4-month), adult (6-month), and old (1-year) Mkk4(ACKO) mice with age-matched control littermates (Mkk4(F/F)). Aging Mkk4(ACKO) mice were more susceptible to atrial tachyarrhythmias than the corresponding Mkk4(F/F) mice, showing characteristic slow and dispersed atrial conduction, for which modeling studies demonstrated potential arrhythmic effects. These differences paralleled increased interstitial fibrosis, upregulated transforming growth factor beta 1 (TGF-β1) signaling and dysregulation of matrix metalloproteinases in Mkk4(ACKO), compared to Mkk4(F/F), atria. Mkk4 inactivation increased the sensitivity of cultured cardiomyocytes to angiotensin II-induced activation of TGF-β1 signaling. This, in turn, enhanced expression of profibrotic molecules in cultured cardiac fibroblasts, suggesting cross-talk between these two cell types in profibrotic signaling. Finally, human atrial tissues in AF showed a Mkk4 downregulation associated with increased production of profibrotic molecules, compared to findings in tissue from control subjects in sinus rhythm.


CONCLUSIONS
These findings together demonstrate, for the first time, that Mkk4 is a negative regulator of the TGF-β1 signaling associated with atrial remodeling and arrhythmogenesis with age, establishing Mkk4 as a new potential therapeutic target for treating AF.
Institute of Cardiovascular Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Manchester, UK.
Laura
L
Davies
Jiawei
J
Jin
Weijin
W
Shen
Hoyee
H
Tsui
Ying
Y
Shi
Yanwen
Y
Wang
Yanmin
Y
Zhang
Guoliang
G
Hao
Jingjing
J
Wu
Si
S
Chen
James A
JA
Fraser
Nianguo
N
Dong
Vincent
V
Christoffels
Ursula
U
Ravens
Christopher L-H
CL
Huang
Henggui
H
Zhang
Elizabeth J
EJ
Cartwright
Xin
X
Wang
Ming
M
Lei
D000367:Age Factors; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001281:Atrial Fibrillation / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D064752:Atrial Remodeling / Q000187:drug effects; D016022:Case-Control Studies; D002478:Cells, Cultured; D003198:Computer Simulation; D015536:Down-Regulation; D005260:Female; D005355:Fibrosis; D006339:Heart Rate; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse
aging; atrial fibrillation; cardiac remodeling