coronary artery sclerosis, myocardial and kidney fibrosis in ZDF rats
As mentioned above, complications are one of the main causes of death in patients with diabetes, and whether anti-diabetes drugs can alleviate these complications has become an important consideration in the development of such drugs. The main complication of diabetes is coronary artery sclerosis (Ikonomidis et al., 2016; Naito & Miyauchi, 2017). Using H&E and periodic acid-Schiff staining, we found that the CAG -treated mice had thinner coronary arteries than the vehicle group (Figure 4A and 4B). The thinning effect on the coronary arteries of CAG was even stronger than that of Dapagliflozin. This result corresponded to an increase in the plasma HDL-c/LDL-c ratio in rats treated withCAG (Figure 3I), suggesting that CAG can effectively reverse coronary atherosclerosis.
Also, epidemiological studies have shown that with the development of diabetes, multiple tissues collapse, such as myocardial fibrosis and renal degeneration, which can also lead to cardiovascular complications and diabetic nephropathy (Pop-Busui et al., 2017). We then determined the protective effects of CAG on cardiovascular and nephropathy complications in ZDF rats. By using the Sirius staining (for collagen) and Masson staining (for fiber), a significant accumulation of collagen in the heart, which is a pathologic indicator of myocardium fibrosis, was observed in the vehicle group (as indicated by the black arrow in Figure 5A), compared with the lean group. Dapagliflozin and CAG could efficiently decrease collagen and fiber to a similar level of that in the lean mice (Figure 5A-5C). These ameliorating effects were well coincided with their effects in reducing myocardial fibrosis in ZDF diabetes rats. These two compounds have also been shown to relieve fibrosis in the kidney similar to that in the heart. (Figure 5D-5F). Immunohistochemistry analysis of TGF-β1 protein, a representative biomarker of fibrosis, further confirmed the anti-fibrosis effects of CAG in the heart and the kidney as indicated by a significant decrease in the expression of TGF-β1 (Figure 5G-5H).