Zheng Cheng1, Mingming Zhang1, Jianqiang Hu1, Jie Lin1, Xinyu Feng1, Shanjie Wang1, Tingting Wang1, Erhe Gao2, Haichang Wang3, Dongdong Sun4. 1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. 2. Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA. 3. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: wanghc@fmmu.edu.cn. 4. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: wintersun3@gmail.com.
Abstract
AIMS: Angiotension II (Ang II) plays a central role in the pathogenesis of renin-angiotensin-aldosterone system (RAAS)-induced heart failure. Mst1 exerts its function in cardiomyocytes subjected to pathological stimuli via inhibiting autophagy and aggravating apoptosis, but its role in RAAS-mediated cardiac injury is still unknown. Here, we aimed to determine whether cardiomyocyte-specific Mst1 knockout can alleviate Ang II-induced cardiac injury by improving cardiomyocyte autophagy and whether these functions depend on Ang II receptors. RESULTS: Mst1 knockout alleviated Ang II-induced heart failure, without affecting blood pressure and compensatory concentric hypertrophy. Mst1 specific knockout improved the effects of Ang II on cardiomyocyte autophagy, as evidenced by further increased LC3-II expression and decreased P62 expression. More typical autophagosomes accompanied by less damaged mitochondria were also observed by electron microscopy in Ang II-treated Mst1Δ/Δ mice. In vitro, Mst1 knockdown promoted cardiomyocyte autophagic flux, as demonstrated by more GFP-mRFP-LC3 puncta per cell. Increased LC3-II and decreased P62 expression both in the presence and absence of chloroquine were observed in Mst1 knockdown cardiomyocytes administered with Ang II. Treatment with 3-MA, an inhibitor of autophagy, abolished the beneficial effects of Mst1 knockout against Ang II-induced cardiac dysfunction. The compensatory effects of Ang II on upregulated autophagy were associated with Mst1 inhibition. Interestingly, the knockdown or antagonization of AT1R inhibited cardiomyocyte autophagy, which may represent a threat to cardiac function. Importantly, Mst1 knockout consistently enhanced cardiomyocyte autophagy following the knockdown or blocking of AT1R and AT2R. CONCLUSION: Cardiomyocyte-specific Mst1 knockout alleviates Ang II-induced cardiac injury by enhancing cardiomyocyte autophagy. Mst1 inhibition may counteract the undesirable effects of Ang II receptors blockage on cardiomyocyte autophagy and represent a promising complementary treatment strategy against Ang II-induced cardiac injury.
AIMS: Angiotension II (Ang II) plays a central role in the pathogenesis of renin-angiotensin-aldosterone system (RAAS)-induced heart failure. Mst1 exerts its function in cardiomyocytes subjected to pathological stimuli via inhibiting autophagy and aggravating apoptosis, but its role in RAAS-mediated cardiac injury is still unknown. Here, we aimed to determine whether cardiomyocyte-specific Mst1 knockout can alleviate Ang II-induced cardiac injury by improving cardiomyocyte autophagy and whether these functions depend on Ang II receptors. RESULTS:Mst1 knockout alleviated Ang II-induced heart failure, without affecting blood pressure and compensatory concentric hypertrophy. Mst1 specific knockout improved the effects of Ang II on cardiomyocyte autophagy, as evidenced by further increased LC3-II expression and decreased P62 expression. More typical autophagosomes accompanied by less damaged mitochondria were also observed by electron microscopy in Ang II-treated Mst1Δ/Δ mice. In vitro, Mst1 knockdown promoted cardiomyocyte autophagic flux, as demonstrated by more GFP-mRFP-LC3 puncta per cell. Increased LC3-II and decreased P62 expression both in the presence and absence of chloroquine were observed in Mst1 knockdown cardiomyocytes administered with Ang II. Treatment with 3-MA, an inhibitor of autophagy, abolished the beneficial effects of Mst1 knockout against Ang II-induced cardiac dysfunction. The compensatory effects of Ang II on upregulated autophagy were associated with Mst1 inhibition. Interestingly, the knockdown or antagonization of AT1R inhibited cardiomyocyte autophagy, which may represent a threat to cardiac function. Importantly, Mst1 knockout consistently enhanced cardiomyocyte autophagy following the knockdown or blocking of AT1R and AT2R. CONCLUSION: Cardiomyocyte-specific Mst1 knockout alleviates Ang II-induced cardiac injury by enhancing cardiomyocyte autophagy. Mst1 inhibition may counteract the undesirable effects of Ang II receptors blockage on cardiomyocyte autophagy and represent a promising complementary treatment strategy against Ang II-induced cardiac injury.
Authors: Valeria Marrocco; Julius Bogomolovas; Elisabeth Ehler; Cristobal G Dos Remedios; Jiayu Yu; Chen Gao; Stephan Lange Journal: J Mol Cell Cardiol Date: 2019-02-08 Impact factor: 5.000
Authors: Kalhara R Menikdiwela; Latha Ramalingam; Fahmida Rasha; Shu Wang; Jannette M Dufour; Nishan S Kalupahana; Karen K S Sunahara; Joilson O Martins; Naima Moustaid-Moussa Journal: Cell Death Dis Date: 2020-02-03 Impact factor: 8.469