Qingda granule attenuates angiotensin II-induced cardiac hypertrophy and apoptosis and modulates the PI3K/AKT pathway

Cheng, Ying; Shen, Aling; Wu, Xiangyan; Shen, Zhiqing; Chen, Xiaoping; Li, Jiapeng; Liu, Liya; Lin, Xiaoying; Chen, Youqin; Chu, Jianfeng; Peng, Jun

doi:10.1016/j.biopha.2020.111022

Cited by 41 publications

(27 citation statements)

References 39 publications

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“…Qingda granule (QDG) is a simplified formulation based on Qingxuan Jiangya Decoction (QXJYD), prescribed by academician Ke-ji Chen, which is a well-known traditional Chinese medicine formula to treat hypertension for more than 60 years in China (Yu et al, 2020;Zhang et al, 2020;Cheng et al, 2021). QDG is composed of Gastrodia elata Blume (Tianma), Uncaria rhynchophylla (Miz.)…”

Section: Introductionmentioning

confidence: 99%

Qingda Granule Attenuates Angiotensin II-Induced Blood Pressure and Inhibits Ca2+/ERK Signaling Pathway

Cheng

Shen

et al. 2021

Front. Pharmacol.

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Objective: As a well-known traditional Chinese medicine formula prescribed by academician Ke-ji Chen, Qingda granule (QDG) lowered the blood pressure of spontaneously hypertensive rats and attenuated hypertensive cardiac remodeling and inflammation. However, its functional role and underlying mechanisms on hypertensive vascular function remain largely unclear. This study aims to assess the effects of QDG treatment on Angiotensin II- (AngII-) induced hypertension and vascular function and explore its underlying mechanisms both in vitro and in vivo.Methods: In an in vivo study, 25 male C57BL/6 mice were randomly divided into five groups, including Control, AngII, AngII + QDG-L, AngII + QDG-M, and AngII + QDG-H groups (n = 5 for each group). Mice in AngII and AngII + QDG-L/-M/-H groups were infused with AngII (500 ng/kg/min), while in the Control group, they were infused with saline. Mice in AngII + QDG were intragastrically given different concentrations of QDG (0.5725, 1.145, or 2.29 g/kg/day), while in Control and AngII groups, they were intragastrically given equal volumes of double distilled water for 2 weeks. Blood pressure was determined at 0, 1, and 2 weeks of treatment. Ultrasound was used to detect the pulse wave velocity (PWV) and HE staining to detect the pathological change of the abdominal aorta. RNA sequencing (RNA-seq) was performed to identify the differentially expressed transcripts (DETs) and related signaling pathways. IHC was used to detect the expression of p-ERK in the abdominal aorta. Primary isolated rat vascular smooth muscle cells (VSMCs) were used to assess the cellular Ca2+ release and activation of the ERK pathway by confocal microscope and western blotting analysis, respectively.Results: QDG treatment significantly alleviated the elevated blood pressure, the PWV, and the thickness of the abdominal aorta in AngII-induced hypertensive mice. RNA-seq and KEGG analyses identified 1,505 DETs and multiple enriched pathways (including vascular contraction and calcium signaling pathway) after QDG treatment. Furthermore, confocal microscope showed that QDG treatment partially attenuated the increase of Ca2+ release with the stimulation of AngII in cultured VSMCs. In addition, IHC and western blotting indicated that QDG treatment also partially alleviated the increase of phospho-ERK levels in abdominal aorta tissues of mice and cultured VSMCs after the infusion or stimulation of AngII.Conclusion: QDG treatment attenuated the elevation of blood pressure, abdominal aorta dysfunction, pathological changes, Ca2+ release, and activation of the ERK signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Qingda Granule Attenuates Angiotensin II-Induced Blood Pressure and Inhibits Ca2+/ERK Signaling Pathway

Cheng

Shen

et al. 2021

Front. Pharmacol.

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“…Apoptosis is known to contribute to various cardiovascular diseases, including heart failure, myocardial infarct, and reperfusion injury [ 35 , 36 ]. Previous research has also shown that cardiac hypertrophy is related to a reduced cell number due to enhanced apoptosis [ 37 , 38 ]. In addition, oxidative stress has been shown to be responsible for cardiomyocyte apoptosis [ 39 – 41 ].…”

Section: Discussionmentioning

confidence: 99%

Peroxiredoxin-5 Knockdown Accelerates Pressure Overload-Induced Cardiac Hypertrophy in Mice

Dai

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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A recent study showed that peroxiredoxins (Prxs) play an important role in the development of pathological cardiac hypertrophy. However, the involvement of Prx5 in cardiac hypertrophy remains unclear. Therefore, this study is aimed at investigating the role and mechanisms of Prx5 in pathological cardiac hypertrophy and dysfunction. Transverse aortic constriction (TAC) surgery was performed to establish a pressure overload-induced cardiac hypertrophy model. In this study, we found that Prx5 expression was upregulated in hypertrophic hearts and cardiomyocytes. In addition, Prx5 knockdown accelerated pressure overload-induced cardiac hypertrophy and dysfunction in mice by activating oxidative stress and cardiomyocyte apoptosis. Importantly, heart deterioration caused by Prx5 knockdown was related to mitogen-activated protein kinase (MAPK) pathway activation. These findings suggest that Prx5 could be a novel target for treating cardiac hypertrophy and heart failure.

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“…An osmotic minipump (Alzet model 2004) was implanted subcutaneously to infuse Ang II (Ang II 500 ng/kg/min) or vehicle control (0.9% saline) for 4 weeks. Ang II (500 ng/kg/min) was used in our experiment according to previous reports [ 15 , 16 ]. The mice were allowed to recover with free access to food and drinking water.…”

Section: Methodsmentioning

confidence: 99%

Nlrp3 Deficiency Alleviates Angiotensin II‐Induced Cardiomyopathy by Inhibiting Mitochondrial Dysfunction

Chen

Zeng

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Inflammation has been considered a key component in the pathogenesis and progression of angiotensin II- (Ang II-) induced cardiac hypertrophy and related cardiomyopathy. As a vital mediator of inflammation, the role of the Nlrp3 inflammasome in Ang II-induced cardiomyopathy remains unclear. This study was aimed to determine whether Nlrp3 inflammasome activation and its downstream pathway were involved in Ang II-induced cardiomyopathy. We established an Ang II infusion model in both wild-type and Nlrp3-/- mice to determine the contribution of Nlrp3 to cardiac function. Cardiac fibrosis was determined by Masson’s trichrome staining, real-time PCR, and TUNEL assay; cardiac function was assessed by echocardiography. Nlrp3 inflammasome activation and related downstream cytokines were measured by Western blotting and enzyme-linked immunosorbent assays; mitochondrial dysfunction was examined by transmission electron microscopy and real-time PCR. We found that Ang II-infused mice showed impaired cardiac function, as evidenced by increased cardiac fibrosis, apoptosis, inflammation, and left ventricular dysfunction. However, these alterations were significantly alleviated in the mice with Nlrp3 gene deletion. Moreover, Ang II-infused mice showed increased Nlrp3 inflammasome activity relative to that of the cytokines IL-1β and IL-18, increased reactive oxygen species, mitochondrial abnormalities, and decreased mtDNA copy number and ATP synthase activity. These molecular and pathological alterations were also attenuated in Nlrp3 deficient mice. In conclusion, Nlrp3 inflammasome-induced mitochondrial dysfunction is involved in Ang II-induced cardiomyopathy. Nlrp3 gene deletion attenuated mitochondrial abnormalities, cardiac inflammation, oxidative stress, and fibrosis and thus alleviated heart dysfunction and hypertrophy. Targeting the Nlrp3 inflammasome and/or mitochondria may be a therapeutic approach for Ang II-induced cardiac diseases.

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Qingda granule attenuates angiotensin II-induced cardiac hypertrophy and apoptosis and modulates the PI3K/AKT pathway

Cited by 41 publications

References 39 publications

Qingda Granule Attenuates Angiotensin II-Induced Blood Pressure and Inhibits Ca2+/ERK Signaling Pathway

Qingda Granule Attenuates Angiotensin II-Induced Blood Pressure and Inhibits Ca2+/ERK Signaling Pathway

Peroxiredoxin-5 Knockdown Accelerates Pressure Overload-Induced Cardiac Hypertrophy in Mice

Nlrp3 Deficiency Alleviates Angiotensin II‐Induced Cardiomyopathy by Inhibiting Mitochondrial Dysfunction

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