TY  - JOUR
A1  - Schnelle, Moritz
A1  - Sawyer, Iain
A1  - Anilkumar, Narayana
A1  - Mohamed, Belal A.
A1  - Richards, Daniel A.
A1  - Toischer, Karl
A1  - Zhang, Min
A1  - Catibog, Norman
A1  - Sawyer, Greta
A1  - Mongue-Din, Héloïse
A1  - Schröder, Katrin
A1  - Hasenfuß, Gerd
A1  - Shah, Ajay M.
T1  - NADPH oxidase-4 promotes eccentric cardiac hypertrophy in response to volume overload
T2  - Cardiovascular research
N2  - Aims: Chronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling.
Methods and results: We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4−/−) vs. wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4−/− mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs. 0.27, P < 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs. 43%, P < 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm2 vs. 379 μm2, P < 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density, and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice, whereas levels decreased in Nox4−/− mice (+29% vs. −21%, P < 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4−/− mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A.
Conclusion: Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.
KW  - NADPH oxidase
KW  - Volume overload
KW  - Heart
KW  - Mouse models
KW  - Cardiac remodelling
KW  - cardiac myocytes
KW  - myocardium
KW  - cardiomegaly
KW  - nadp
KW  - phosphorylation
KW  - mice
KW  - excess fluid volume
KW  - proto-oncogene proteins c-akt
KW  - shunt
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63318
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-633187
SN  - 1755-3245
VL  - 117
IS  - 1
SP  - 178
EP  - 187
PB  - Oxford University Press
CY  - Oxford
ER  -