NADPH oxidase-4 promotes eccentric cardiac hypertrophy in response to volume overload
2019 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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NADPH oxidase-4 promotes eccentric cardiac hypertrophy in response to volume overload
Schnelle, M. ; Sawyer, I.; Anilkumar, N.; Mohamed, B. A. ; Richards, D. A.; Toischer, K. & Zhang, M. et al. (2019)
Cardiovascular Research, 117(1) pp. 178-187. DOI: https://doi.org/10.1093/cvr/cvz331
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Details
- Authors
- Schnelle, Moritz ; Sawyer, Iain; Anilkumar, Narayana; Mohamed, Belal A. ; Richards, Daniel A.; Toischer, Karl ; Zhang, Min; Catibog, Norman; Sawyer, Greta; Mongue-Din, Héloïse; Schröder, Katrin; Hasenfuss, Gerd ; Shah, Ajay M.
- Abstract
- 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.
- Issue Date
- 2019
- Journal
- Cardiovascular Research
- Project
- SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur
SFB 1002 | D04: Bedeutung der Methylierung von RNA (m6A) und des Histons H3 (H3K4) in der Herzinsuffizienz - Working Group
- RG Hasenfuß (Transition zur Herzinsuffizienz)
RG Toischer (Kardiales Remodeling) - ISSN
- 0008-6363
- eISSN
- 1755-3245
- Language
- English