Nox4 inhibition with GKT137831 protects against diabetic cardiomyopathy: Insights from functional and transcriptomic analysis

Objective

NADPH oxidase 4 (Nox4) is abundantly expressed in the heart and is the primary source of reactive oxygen species (ROS) in the cardiac tissue associated with cardiovascular diseases. We sought to determine whether Nox4 plays a major role in modulating diabetic cardiomyopathy (DCM) and the mechanisms involved.

Research design and methods

Diabetes was induced in male Wistar rats with a single dose of streptozotocin, followed by a daily dose of GKT137831 for 3 months. The characteristics of DCM were evaluated by electrocardiography (ECG) and hemodynamic measurements. Western blot analysis, histopathological evaluation, and immunohistochemical staining were performed to assess ROS, fibrosis, and apoptosis. Additionally, transcriptome analysis via RNA sequencing was conducted to investigate the role of Nox4 in cardiac dysfunction in diabetic rats.

Results

Rats with DCM presented significant left ventricular dysfunction with elevated levels of cardiac damage markers, Nox4 expression, ROS, cardiac fibrosis markers, and apoptotic proteins. We found that treatment with the Nox4 specific inhibitor GKT137831 ameliorated effects in DCM. These anatomic findings were accompanied by significant improvements in cardiac function. Furthermore, RNA sequencing revealed that GKT137831 treatment prevented the upregulation of genes associated with contractility abnormalities, such as Myl4, Cacna2d2, Cacnb3, Atp2a1, Cox6b2, Cacnb1, and Cacna2d3 in the diabetic cardiac tissue.

Conclusion

Nox4 inhibition with GKT137831 may exert a protective effect on DCM by improving cardiac dysfunction, indicating its translational value in clinical settings.