Background Chronic heart failure (CHF) is a major cause of mortality in diabetes due to characteristic alterations in cardiac structure and function. The diabetic heart is typified by increased fibrosis, inflammation and microvascular remodelling together with hyperglycaemia-induced endothelial dysfunction and reactive oxygen species (ROS) generation, which may predispose to cardiovascular stress. The aim of this study was to investigate the specific contribution of endothelial Nox4 NADPH oxidase, a major source of cardiovascular ROS, to cardiac remodelling in experimental diabetes.

Methods Diabetes was induced in endothelial-specific Nox4 transgenic (Tg) mice and WT littermate controls (10–12 weeks of age; n=8–12/group) by streptozotocin (STZ) injection. After 6 months, echocardiography was performed and blood and cardiac tissue collected for metabolic and gene expression analyses, respectively.

Results Endothelial Nox4 overexpression did not affect blood glucose or HbA1c levels in control or diabetic animals. Significant diastolic dysfunction was observed in WT STZ mice (E/A ratio: control 1.6±0.09 versus STZ 1.3±0.04). However, whilst Tg control mice demonstrated impaired diastolic function (E/A ratio: 1.6±0.09 vs 1.4±0.08), no further dysfunction was seen with experimental diabetes. Consistent with basal diastolic dysfunction, CTGF and MMP2 expression were increased in Tg control animals, without being further altered by STZ, whereas CTGF was increased in WT STZ animals versus controls. Interestingly, increased expression (compared to WT control animals) of SOD1 (WT 31%±6.3%, Tg 78%±24%) and catalase (WT 24%±14%, Tg 85%±28%) seen in STZ diabetes was greater in Tg than in WT mice, which is likely to at least partly explain protection against further diastolic dysfunction.

Conclusion These data indicate that endothelial Nox4 NADPH oxidase may protect against adverse cardiac remodelling and dysfunction in experimental diabetes, thereby highlighting this major ROS source as a potential therapeutic target for CHF in diabetes.