Berberine attenuates cardaic fibrosis via downregulating IGF1R in diabetic rats
Guohua Li Ling Dong Feng Gao
1.Department of Aerospace Medicine, Fourth Military Medical University, Xi’an 710032, China
Objectives: Diabetic cardiac fibrosis increases ventricular stiffness and facilitates occurrence of diastolic and systolic dysfunction. IGF 1R is a key receptor regulating cell growth, survival and differentiation. However, the role of IGF 1R and its downstream signaling in pathogenesis of diabetic cardiac fibrosis is rarely known. Berberine, a natural isoquinoline alkaloid, can yield benefits to cardiovascular system in diabetes. This study aimed to investigate whether berberine could alleviate interstitial fibrosis in diabetic heart and the underlying mechanisms.
Methods: Diabetes was induced by streptozotocin and high fat diet in male Sprague Dawley rats. Then, diabetes rats were gavaged with berberineor saline for 4 weeks. Cardiac function and fibrosis were measured. Effects of berberine on fibroblast proliferation and differentiation were studied in isolated neonatal cardiac fibroblasts cultured in high glucose medium.
Results: Diabetic rats presented cardiac systolic dysfunction and matrix collagen deposition, with decreased ejection fraction and fraction of shortening, increased expression of TGF beta, fibronectin, collagen 1, alpha SMA andMMP 2, MMP 9. Gavage of berberine for 4 weeks ameliorated cardiac systolic dysfunction and interstitial fibrosis in diabetic rats. Furthermore, the upregulation of IGF1R was inhibited by berberine in diabetic heart. In vitro data demonstrated that berberine inhibited proliferation of fibroblast and up-regulation of IGF1R and MMP 2, MMP 9 induced by high glucose. Furthermore, the inhibitory effects of berberine on MMP 2, MMP9 were blunted by overexpression of IGF1R in myocardial fibroblasts.
Conclusions: Increased IGF1R contributes to cardiac fibrosis through up-regulating MMP 2, MMP9 in diabetic rats, and berberine attenuates cardiac fibrosis through down-regulating IGF1R to decrease MMP 2, MMP9 in diabetes.