Objectives To investigate the potential protective effect of Bosentan in diabetic cardiac complications.
Methods Male C57BL/6 mice with 6-week old were divided into 3 groups (N = 20) : Control group, DM group (diabetes group) and DM-B group (diabetes with Bosentan group). STZ was injected as 200 mg/Kg for single dose, i.p. (intraperitoneal injection). Fasting blood glucose (FBG) was measured at 0-, 1-, 2-week after STZ injection to confirm that diabetic model was made. Bosentan (100 mg/Kg) and placebo was given i.g. (intragastric administration) once a day immediately after STZ injection for 18 weeks. Cardiac fibrosis was evaluated by morphometric analysis and electron microscopy. The differences of mRNA expression were compared by real-time PCR. Cardiac systolic function was evaluated by echocardiography.
Results After 18 weeks of diabetic situation, FBG of DM-B mice was significantly higher than that of Control mice and was similar with that of DM mice (DM mice vs. control mice, P < 0.001; DM-B vs. control mice, P < 0.001; DM mice vs. DM-B mice, P > 0.05). Pathological analysis with Masson’s Trichrome staining showed significant fibrotic changes in diabetic myocardium, and the fibrosis was ameliorated by Bosentan. Electron microscopy study revealed a disruption of sarcomere and myofibril structure in myocardium of DM mice, which is partially prevented by Bosentan. Furthermore, area of interstitial fibrosis is markedly lower in DM-B mice. This lower area of interstitial fibrosis is associated with higher expression of cardiac VEGF mRNA (a potent angiogenic factor) in DM-B mice than DM mice (P < 0.01). The heart of DM-B mice also showed lower expression of fibrotic genes (TGF-ß, CTGF and Collagen-1) than DM mice (P < 0.01). Furthermore, cardiac systolic function (fractional shortening, FS) of DM and DM-B mice decreased after 18 weeks of diabetes (DM vs Control mice, P < 0.001). However, the impairment of cardiac function (FS) was significantly ameliorated, even nearly normalised by Bosentan (DM-B vs Control mice, P > 0.05).
Conclusions These findings indicate the potential usefulness of an ET receptor antagonist Bosentan in the amelioration of diabetic cardiac complications (myocardial fibrosis and cardiac dysfunction) without affecting blood glucose. This may provide a promising therapeutical strategy for diabetic heart disease.