Luopei Wang1, Ding Yuan2, Jie Zheng1, Xuecui Wu1, Juntao Wang1, Xiu Liu1, Yumin He1, Changcheng Zhang1, Chaoqi Liu1, Ting Wang3, Zhiyong Zhou4. 1. Medical College of China Three Gorges University, Yichang 443002, PR China. 2. RENHE Hospital of China Three Gorges University, Yichang 443000, PR China. 3. Medical College of China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of ischemic cardiovascular and cerebrovascular disease translational medicine (Three Gorges University), Yichang 443000, PR China. Electronic address: tingting0301@126.com. 4. Medical College of China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of ischemic cardiovascular and cerebrovascular disease translational medicine (Three Gorges University), Yichang 443000, PR China. Electronic address: in_bud@ctgu.edu.cn.
Abstract
BACKGROUND: Myocardial fibrosis is a common pathological manifestation of many cardiovascular diseases at the end stage. Autophagy has been demonstrated to play a protective role in the cardiac fibrosis. Our previous studies have demonstrated that the Saponins from Panax japonicus effectively ameliorated the degree of fibrosis in rat acute myocardial ischemia injury model though the mechanisms are not clear. HYPOTHESIS: We hypothesized that Chikusetsusaponin IVa (CS), a major component of Saponins from Panaxjaponicus, may improve isoprenaline induced myocardial fibrosis via AMPK/mTOR/ULK1 mediated autophagy METHODS: Continuous subcutaneous injection of isoproterenol for 21 days was used to induce myocardial fibrosis in mice and high and low doses (15 mg/kg and 5 mg/kg) of CS was administered by oral gavage to observe the efficacy. Animals were sacrificed 12 h after the last administration and samples were collected. H&E staining, Masson staining and wheat germ agglutinin (WGA) staining were used to evaluate histopathological changes, collagen deposition and myocardial cell hypertrophy. Autophagy-related markers (LC3β, Beclin1 and p62) and AMPK/mTOR/ULK1 pathway-related markers were evaluated by western blot. RESULTS: CS effectively attenuated isoprenaline-induced myocardial fibrosis in vivo, reduced the heart index, inhibited inflammatory infiltration, decreased collagen deposition and myocardial cell size. CS treatment rescued the expression of autophagy-related markers. CS activated autophagy through the activation of AMPK, which in turn inhibited the phosphorylation of mTOR and ULK1(Ser757), rather than directly phosphorylate ULK1(Ser555) by AMPK. CONCLUSION: Our data demonstrated that CS attenuated isoprenaline-induced myocardial fibrosis by activating autophagy through AMPK/mTOR/ULK1 pathway. Our findings suggested that CS is a potential candidate drug against cardiac fibrosis and have identified potential drug targets for the treatment of heart diseases.
BACKGROUND:Myocardial fibrosis is a common pathological manifestation of many cardiovascular diseases at the end stage. Autophagy has been demonstrated to play a protective role in the cardiac fibrosis. Our previous studies have demonstrated that the Saponins from Panax japonicus effectively ameliorated the degree of fibrosis in rat acute myocardial ischemia injury model though the mechanisms are not clear. HYPOTHESIS: We hypothesized that Chikusetsusaponin IVa (CS), a major component of Saponins from Panaxjaponicus, may improve isoprenaline induced myocardial fibrosis via AMPK/mTOR/ULK1 mediated autophagy METHODS: Continuous subcutaneous injection of isoproterenol for 21 days was used to induce myocardial fibrosis in mice and high and low doses (15 mg/kg and 5 mg/kg) of CS was administered by oral gavage to observe the efficacy. Animals were sacrificed 12 h after the last administration and samples were collected. H&E staining, Masson staining and wheat germ agglutinin (WGA) staining were used to evaluate histopathological changes, collagen deposition and myocardial cell hypertrophy. Autophagy-related markers (LC3β, Beclin1 and p62) and AMPK/mTOR/ULK1 pathway-related markers were evaluated by western blot. RESULTS:CS effectively attenuated isoprenaline-induced myocardial fibrosis in vivo, reduced the heart index, inhibited inflammatory infiltration, decreased collagen deposition and myocardial cell size. CS treatment rescued the expression of autophagy-related markers. CS activated autophagy through the activation of AMPK, which in turn inhibited the phosphorylation of mTOR and ULK1(Ser757), rather than directly phosphorylate ULK1(Ser555) by AMPK. CONCLUSION: Our data demonstrated that CS attenuated isoprenaline-induced myocardial fibrosis by activating autophagy through AMPK/mTOR/ULK1 pathway. Our findings suggested that CS is a potential candidate drug against cardiac fibrosis and have identified potential drug targets for the treatment of heart diseases.
Authors: Michelle R Santoso; Gentaro Ikeda; Yuko Tada; Ji-Hye Jung; Evgeniya Vaskova; Raymond G Sierra; Cornelius Gati; Andrew B Goldstone; Daniel von Bornstaedt; Praveen Shukla; Joseph C Wu; Soichi Wakatsuki; Y Joseph Woo; Phillip C Yang Journal: J Am Heart Assoc Date: 2020-03-05 Impact factor: 5.501