LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway

Peng, Shi; Lu, Xiaofeng; Qi, Yiding; Li, Jing; Xu, Juan; Yuan, Tianyou; Wu, Xiaoyu; Ding, Yu; Li, Wenhua; Zhou, Genqing; Wei, Yong; Li, Jun; Chen, Songwen; Liu, Shaowen

doi:10.1155/2020/9815039

Cited by 31 publications

(25 citation statements)

References 46 publications

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“…Previous studies have found that Ang II cause hypertension and hypertensive cardiac hypertrophy and fibrosis 23,24 . SIRT3 can protect the heart from multiple types of diseases which cause cardiac hypertrophy and fibrosis, through the regulation of oxidative stress, metabolism and aging 14,25‐27 . It was consistent with the previous study that SIRT3 deficiency aggravated Ang II‐induced heart injury.…”

Section: Discussionsupporting

confidence: 89%

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

Zhang¹,

Li²,

Suo³

et al. 2021

J Cellular Molecular Medi

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Lymphangiogenesis is possibly capable of attenuating hypertension‐induced cardiac injury. Sirtuin 3 (SIRT3) is an effective mitochondrial deacetylase that has the potential to modulate this process; however, its role in hypertension‐induced cardiac lymphangiogenesis to date has not been investigated. Our experiments were performed on 8‐week‐old wild‐type (WT), SIRT3 knockout (SIRT3‐KO) and SIRT3 overexpression (SIRT3‐LV) mice infused with angiotensin II (Ang II) (1000 ng/kg per minute) or saline for 28 days. After Ang II infusion, SIRT3‐KO mice developed a more severe cardiac remodelling, less lymphatic capillaries and lower expression of lymphatic marker when compared to wild‐type mice. In comparison, SIRT3‐LV restored lymphangiogenesis and attenuated cardiac injury. Furthermore, lymphatic endothelial cells (LECs) exposed to Ang II in vitro exhibited decreased migration and proliferation. Silencing SIRT3 induced functional decrease in LECs, while SIRT3 overexpression LECs facilitated. Moreover, SIRT3 may up‐regulate lymphangiogenesis by affecting vascular endothelial growth factor receptor 3 (VEGFR3) and ERK pathway. These findings suggest that SIRT3 could promote lymphangiogenesis and attenuate hypertensive cardiac injury.

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Section: Discussionsupporting

confidence: 89%

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

Zhang¹,

Li²,

Suo³

et al. 2021

J Cellular Molecular Medi

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“…Recently, we reported that LCZ696, but not valsartan, ameliorated isoproterenol-induced fibrosis in rats 14 . Other experimental studies showed that LCZ696 ameliorated oxidative stress in rodent models of obesity-related and diabetic cardiomyopathy, myocardial infarction, and pressure overload-induced cardiac remodeling 15 – 18 . Ge et al reported that LCZ696 inhibits the nuclear transport of nuclear factor-κB and phosphorylation of c-Jun N-terminal kinase and p38 mitogen-activated kinase in H9c2 cardiomyocytes under high-glucose conditions 16 .…”

Section: Introductionmentioning

confidence: 97%

LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats

Miyoshi

Nakamura

Amioka

et al. 2022

Sci Rep

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Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor–neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague–Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.

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“…However, the pretreatment of LCZ696 in our model ameliorated Sirt3 expression, thus, the myocardial injury caused by trastuzumab was effectively inhibited. In a pressure overload-induced heart failure model, LCZ696 could induced the upregulation of MnSOD through a Sirt3-dependent pathway [22] . We found that, in trastuzumab-induced H9C2 cell model, LCZ696 could increase the mRNA expression of SOD2 and reduce the content of MDA, and then, the uorescence intensity of ROS was inhibited measured by ow cytometry.…”

Section: Discussionmentioning

confidence: 97%

LCZ696 Attenuates ROS/NLRP3 Mediated Pyroptosis in Trastuzumab-induced H9C2 Cell Model Via Ameliorating Sirt3 Expression

Zang¹,

Bai²,

Lou³

et al. 2021

Preprint

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Trastuzumab-induced cardiomyopathy have been a kind of clinical crucial problems in the field of cardio-oncology. LCZ696, clinically named sacubitril/valsartan, was administered to treat the patients with heart failure, so that it may be a substantial prevention to attenuate chemotherapy-induced cardiotoxicity. We firstly confirmed that LCZ696 and trastuzumab can affect the content of Sirt3 and NLRP3 in H9C2 cell, which confirmed the concentration of LCZ696 (10μM) and trastuzumab (100nM). Then H9C2 cells were allocated into 3 groups: (1) Con group; (2) TRA group; (3) TRA+LCZ696 group. We investigated the change of mRNA expression and protein synthesis of cultured H9c2 cardiocardiomyocytes on exposure to trastuzumab alone or plus LCZ696. Meanwhile, it turns out that LCZ696 can ameliorate the mRNA expression and content of Sirt3, inhibit the level of ROS, NLRP3, ACS, Caspase-1 and IL-1β in trastuzumab-induced H9C2 cell model. In summary, LCZ696 reduces the oxidative stress caused by ROS and NLRP3-mediated pyroptosis by protecting the activity of Sirt3 in H9C2 cells.

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LCZ696 Ameliorates Oxidative Stress and Pressure Overload-Induced Pathological Cardiac Remodeling by Regulating the Sirt3/MnSOD Pathway

Cited by 31 publications

References 46 publications

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats

LCZ696 Attenuates ROS/NLRP3 Mediated Pyroptosis in Trastuzumab-induced H9C2 Cell Model Via Ameliorating Sirt3 Expression

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