Miao Chen1, Hongwei Li2, Guoxing Wang3, Xuhua Shen1, Shumei Zhao1, Wen Su1. 1. Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China. 2. Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China. Electronic address: lhw19656@sina.com. 3. Department of Emergency, Beijing Friendship Hospital, Capital Medical University, Beijing, China. Electronic address: 13520240749@163.com.
Abstract
BACKGROUND: Previous studies have shown that the activation of advanced glycation end products (AGEs) contributed to the cardiac fibrosis in diabetic patients. Although it had been reported that statins have beneficial effects on cardiac fibrosis in hypertension and myocardial ischemia models, their effects on AGEs models have not been studied. We aimed to investigate the effects of atorvastatin (Ator) on the AGEs-induced cardiac fibrosis both in vitro and vivo. METHODS: Male Sprague-Dawley rats were randomly divided into four groups: Control, AGEs, Ator or AGEs+Ator. The cardiac function was evaluated with the echocardiography at the second and the third month. Fibrosis area, α-SMA and RAGE expression in cardiac tissue were measured. For in vitro study, rat cardiac fibroblasts were treated with PD98059 (ERK inhibitor), Ator or Ator+GW9662 (PPAR-γ antagonist), and then were stimulated with AGEs. Fibroblasts proliferation, ERK1/2, phosphorylated ERK1/2, α-SMA, and RAGE expression were studied. RESULTS: Compared with the control group, in vivo treatment with Ator significantly retarded the AGEs-induced diastolic function and attenuated cardiac fibrosis, α-SMA, and RAGE over expression induced by AGEs. Consistently, Ator prominently downregulated RAGE and α-SMA, while inhibited phosphorylation of ERK1/2 and fibroblast proliferation induced by AGEs in vitro. The GW9662 neutralized these effects of Ator on cardiac fibroblasts stimulated by AGEs. CONCLUSION: In this study, we demonstrated that AGEs-induced fibroblast proliferation and differentiation were dependent on AGEs-RAGE-ERK1/2 pathway and that atorvastatin could block this pathway via activating PPAR-γ.
BACKGROUND: Previous studies have shown that the activation of advanced glycation end products (AGEs) contributed to the cardiac fibrosis in diabeticpatients. Although it had been reported that statins have beneficial effects on cardiac fibrosis in hypertension and myocardial ischemia models, their effects on AGEs models have not been studied. We aimed to investigate the effects of atorvastatin (Ator) on the AGEs-induced cardiac fibrosis both in vitro and vivo. METHODS: Male Sprague-Dawley rats were randomly divided into four groups: Control, AGEs, Ator or AGEs+Ator. The cardiac function was evaluated with the echocardiography at the second and the third month. Fibrosis area, α-SMA and RAGE expression in cardiac tissue were measured. For in vitro study, rat cardiac fibroblasts were treated with PD98059 (ERK inhibitor), Ator or Ator+GW9662 (PPAR-γ antagonist), and then were stimulated with AGEs. Fibroblasts proliferation, ERK1/2, phosphorylated ERK1/2, α-SMA, and RAGE expression were studied. RESULTS: Compared with the control group, in vivo treatment with Ator significantly retarded the AGEs-induced diastolic function and attenuated cardiac fibrosis, α-SMA, and RAGE over expression induced by AGEs. Consistently, Ator prominently downregulated RAGE and α-SMA, while inhibited phosphorylation of ERK1/2 and fibroblast proliferation induced by AGEs in vitro. The GW9662 neutralized these effects of Ator on cardiac fibroblasts stimulated by AGEs. CONCLUSION: In this study, we demonstrated that AGEs-induced fibroblast proliferation and differentiation were dependent on AGEs-RAGE-ERK1/2 pathway and that atorvastatin could block this pathway via activating PPAR-γ.