Abstract
Background: NADPH oxidase-4 (Nox4) is a reactive oxygen species (ROS)-generating enzyme that has protective effects in the heart through several redox-mediated signalling pathways. We previously identified that a splice variant of Nox4, Nox4D, is nuclear-localised, capable of ROS production, and is expressed in cardiomyocytes. The aim of this project was to investigate the effects of Nox4D in cardiomyocytes in vivo.
Methods and results: We generated mice with inducible cardiomyocyte-specific overexpression of Nox4D (icsNox4D). After tamoxifen induction in adult mice, icsNox4D showed a 10-fold increase in Nox4D protein level in the heart compared to controls, whilst echocardiography revealed similar cardiac structure and function. In vitro overexpression of Nox4D increased proliferation of neonatal rat cardiomyocytes but this was unchanged in adult hearts, as assessed by EdU incorporation and the expression of cell cycle genes. The impact of icsNox4D on the response to MI induced by permanent left anterior descending coronary artery (LAD) ligation was next determined. There were no differences between icsNox4D and control mice in infarct size, LV function or LV remodelling 4 weeks post-MI. Furthermore, this correlated with no differences in the gene expression of hypertrophy or cell cycle markers in icsNox4D in either the infarct border zone or remote zone. Ongoing work is investigating the effects of Nox4D overexpression in cultured adult cardiomyocytes.
Conclusion: Cardiomyocyte-specific overexpression of Nox4D in the adult mouse heart is well tolerated and appears not to induce an obvious detrimental phenotype. The responses of these mice to other stresses should be investigated.
Funding: British Heart Foundation
Methods and results: We generated mice with inducible cardiomyocyte-specific overexpression of Nox4D (icsNox4D). After tamoxifen induction in adult mice, icsNox4D showed a 10-fold increase in Nox4D protein level in the heart compared to controls, whilst echocardiography revealed similar cardiac structure and function. In vitro overexpression of Nox4D increased proliferation of neonatal rat cardiomyocytes but this was unchanged in adult hearts, as assessed by EdU incorporation and the expression of cell cycle genes. The impact of icsNox4D on the response to MI induced by permanent left anterior descending coronary artery (LAD) ligation was next determined. There were no differences between icsNox4D and control mice in infarct size, LV function or LV remodelling 4 weeks post-MI. Furthermore, this correlated with no differences in the gene expression of hypertrophy or cell cycle markers in icsNox4D in either the infarct border zone or remote zone. Ongoing work is investigating the effects of Nox4D overexpression in cultured adult cardiomyocytes.
Conclusion: Cardiomyocyte-specific overexpression of Nox4D in the adult mouse heart is well tolerated and appears not to induce an obvious detrimental phenotype. The responses of these mice to other stresses should be investigated.
Funding: British Heart Foundation
| Original language | English |
|---|---|
| Journal | Journal of Molecular and Cellular Cardiology |
| Volume | 120 |
| Early online date | 4 Aug 2018 |
| DOIs | |
| Publication status | Published - 2018 |