Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts.

Cardiac fibrosis is a major pathological manifestation of diabetic cardiomyopathy (DCM), which leads to cardiac remodeling, dilated cardiomyopathy and congestive heart failure. Human cardiac fibroblasts (HCF) constitute the predominant cell type in the heart and matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are also involved in cardiac fibrosis. However, it is unclear whether high glucose levels affect the expression of MMPs and TIMPs in HCF. Sodium‑glucose cotransporter (SGLT) inhibitors have been developed as therapeutic agents and the anti‑DCM effect of SGLT inhibitors has been demonstrated by previous studies. However, whether SLGT inhibitors protect the diabetic heart by directly inhibiting the SGLTs in HCF in addition to lowering the blood glucose levels, has not yet been determined. In the present study, increased MMP‑2 expression was noted in HCFs in response to high glucose levels, which may be reversed by phlorizin (inhibits both SGLT1 and SGLT2), but not dapagliflozin (inhibits SGLT2). In addition, SGLT1 was revealed to be present in the HCFs and high glucose level was demonstrated to increase SGLT1 expression, which may be attenuated by phlorizin. Therefore it was concluded that high glucose levels induced MMP‑2 expression in the HCFs, potentially by upregulating SGLT1. SGLT1 inhibition may be a novel strategy for the treatment of DCM.