Radix Angelica Sinensis and Radix Hedysari Ultrafiltration Extract Protects against X-Irradiation-Induced Cardiac Fibrosis in Rats

Radiation-induced myocardial fibrosis (RIMF) is the main pathological change associated with radiation-induced heart toxicity after radiation therapy in patients with thoracic tumors. There is an antifibrosis effect of Radix Angelica Sinensis and Radix Hedysari (RAS-RH) ultrafiltration extract from Danggui Buxue decoction (DBD) in X-irradiation-induced rat myocardial fibrosis, and this study aimed to investigate whether that effect correlated with apoptosis and oxidative stress damage in primary rat cardiac fibroblasts; further, the potential mechanisms were also explored. In this study, we first found that the RAS-RH antifibrosis effect was associated with the upregulation of microRNA-200a and the downregulation of TGF-β1/smad3 and COL1α. In addition, we also found that the antifibrosis effect of RAS-RH was related to the induction of apoptosis in primary rat cardiac fibroblasts and to the prevention of damage caused by reactive oxygen species (ROS). Interestingly, primary rat cardiac fibroblasts exposed to X-ray radiation underwent apoptosis less frequently in the absence of RAS-RH. Therefore, RAS-RH has the ability to protect against fibrosis, which could be occurring through the induction of apoptosis and the resistance to oxidative stress in rats with X-irradiation-induced myocardial fibrosis; thus, in a model of RIMF, RAS-RH acts against X-irradiation-induced cardiac toxicity.

Download Full-text

Ultrafiltration Extract of Radix Angelica Sinensis and Radix Hedysari Attenuates Risk of Low-Dose X-Ray Radiation-Induced Myocardial Fibrosis In Vitro

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5580828 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Juan Chang ◽

Chengxu Ma ◽

Huan Guo ◽

Haiqiong Ran ◽

Guolian Chen ◽

...

Keyword(s):

Myocardial Fibrosis ◽

Low Dose ◽

Cardiac Fibroblasts ◽

Pathological Condition ◽

Cardiovascular Complications ◽

Angelica Sinensis ◽

X Ray ◽

X Irradiation ◽

Radiation Induced

The risk of radiation-induced heart damage (RIHD) is a growing concern since recent advances in radiation therapy (RT) for cancer treatments have significantly improved the number of survivors. Radiation-induced myocardial fibrosis (RIMF) is the final pathological condition of RIHD and main change leading to serious cardiovascular complications following RT. The aim of this study was to investigate the effect of ultrafiltration extract of Radix Angelica Sinensis and Radix Hedysari (RAS-RH) on the proliferation, apoptosis, and reactive oxygen species (ROS) of cardiac fibroblasts after X-irradiation in vitro. The RAS-RH extract was from the Danggui Buxue decoction (DBD) in TCM. Primary cardiac fibroblasts were irradiated with 1 Gy X-ray to evaluate the effect of RAS-RH on the expression levels of cell proliferation, apoptosis, ROS, and fibrotic molecules. Our data demonstrated that X-irradiation at 1 Gy resulted in the proliferation of cardiac fibroblasts; RAS-RH attenuated the myocardial fibrosis. Furthermore, X-ray radiation reduced the apoptosis of cardiac fibroblasts; RAS-RH accelerated the apoptosis of these cells after irradiation. In addition, the damage driven by ROS in primary cardiac fibroblasts after irradiation was weakened by RAS-RH and the expression of TGF-β1, Col1, and α-SMA increased after irradiation; RAS-RH decreased the expression of these makers. Overall, these data indicate that low-dose X-ray irradiation boosts myocardial fibrosis, and the effect of RAS-RH protects against fibrosis via attenuating the proliferation and accelerating the apoptosis of myocardial fibroblasts after X-irradiation.

Download Full-text

miR-21 is upregulated, promoting fibrosis and blocking G2/M in irradiated rat cardiac fibroblasts

PeerJ ◽

10.7717/peerj.10502 ◽

2020 ◽

Vol 8 ◽

pp. e10502

Author(s):

Huan Guo ◽

Xinke Zhao ◽

Haixiang Su ◽

Chengxu Ma ◽

Kai Liu ◽

...

Keyword(s):

Myocardial Fibrosis ◽

Target Genes ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Differentially Expressed Gene ◽

Stem Loop ◽

Cardiac Morbidity ◽

Increased Risk ◽

And Function

Background Radiation exposure of the thorax is associated with a greatly increased risk of cardiac morbidity and mortality even after several decades of advancement in the field. Although many studies have demonstrated the damaging influence of ionizing radiation on cardiac fibroblast (CF) structure and function, myocardial fibrosis, the molecular mechanism behind this damage is not well understood. miR-21, a small microRNA, promotes the activation of CFs, leading to cardiac fibrosis. miR-21 is overexpressed after irradiation; however, the relationship between increased miR-21 and myocardial fibrosis after irradiation is unclear. This study was conducted to investigate gene expression after radiation-induced CF damage and the role of miR-21 in this process in rats. Methods We sequenced irradiated rat CFs and performed weighted correlation network analysis (WGCNA) combined with differentially expressed gene (DEG) analysis to observe the effect on the expression profile of CF genes after radiation. Results DEG analysis showed that the degree of gene changes increased with the radiation dose. WGCNA revealed three module eigengenes (MEs) associated with 8.5-Gy-radiation—the Yellow, Brown, Blue modules. The three module eigengenes were related to apoptosis, G2/M phase, and cell death and S phase, respectively. By blocking with the cardiac fibrosis miRNA miR-21, we found that miR-21 was associated with G2/M blockade in the cell cycle and was mainly involved in regulating extracellular matrix-related genes, including Grem1, Clu, Gdf15, Ccl7, and Cxcl1. Stem-loop quantitative real-time PCR was performed to verify the expression of these genes. Five genes showed higher expression after 8.5 Gy-radiation in CFs. The target genes of miR-21 predicted online were Gdf15 and Rsad2, which showed much higher expression after treatment with antagomir-miR-21 in 8.5-Gy-irradiated CFs. Thus, miR-21 may play the role of fibrosis and G2/M blockade in regulating Grem1, Clu, Gdf15, Ccl7, Cxcl1, and Rsad2 post-irradiation.

Download Full-text

Liraglutide Attenuates Myocardial Fibrosis via Inhibition of AT1R-Mediated ROS Production in Hypertensive Mice

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248420942007 ◽

2020 ◽

pp. 107424842094200

Author(s):

Peng Chen ◽

Fen Yang ◽

Wenya Wang ◽

Xiao Li ◽

Dongling Liu ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Blood Sugar ◽

Myocardial Fibrosis ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Reactive Oxygen ◽

The Body ◽

Ros Production ◽

Oxygen Species ◽

Ang Ii

Background/Aims: Glucagon-like peptide-1 receptor agonist liraglutide has been reported to exert cardioprotective effects, but its effect on cardiac fibrosis remains controversial. The aim of this study was to investigate the effects of liraglutide on cardiac fibrosis and potential mechanisms. Methods: C57BL/6 mice (3-month old) were randomly divided into control, hypertension, and hypertension + liraglutide groups. The hypertensive state was created by infusion of Ang II (100 ng/kg·min) for 4 weeks through subcutaneously implanted osmotic pumps. The control mice were infused with saline. Mice were also given vehicle or liraglutide (400 μg/kg·day). Blood pressure (BP), blood sugar, myocardial fibrosis, AT1R expression, and reactive oxygen species (ROS) levels were measured. To further elucidate the mechanisms of fibrosis, mouse cardiac fibroblasts were isolated and treated with liraglutide (300 nM/L) or losartan (10 μM) for 3 hours, followed by Ang II (10−7 M) for additional 12 hours. Reactive oxygen species production and expressions of collagen-1 and -3 were measured. Results: Liraglutide reduced BP and blood sugar but did not affect the body weight of the hypertensive mice. Liraglutide also inhibited collagen accumulation, AT1R expression, and ROS generation in the hearts of the hypertensive mice. In in vitro studies, pretreatment with liraglutide and losartan (as control) markedly inhibited Ang II-induced ROS production and collagen expression in the cultured cardiac fibroblasts. Conclusion: Liraglutide reduces myocardial fibrosis in the hypertensive mice, which appears to be dependent on at least in part inhibition of ROS production.

Download Full-text

Abstract 15671: Adipocyte-derived Exosomal Lncrna Nbr2 Promotes Diabetic Myocardial Fibrosis Through Regulating the Ikba/nf-kb Pathway

Circulation ◽

10.1161/circ.142.suppl_3.15671 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Yue Guo ◽

Xingfeng Xu ◽

Lingling Wu ◽

Xiaodong Zhuang ◽

Xinxue Liao

Keyword(s):

Myocardial Fibrosis ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Epigenetic Mechanism ◽

Ang Ii ◽

Intramyocardial Injection ◽

Underlying Mechanisms ◽

Human Cardiac Fibroblasts ◽

And Function

Introduction: The activation of NF-κB is the dominant process that correlates with the pathogenesis of diabetic cardiomyopathy (DCM). Recently, accumulating evidence shows that long noncoding RNAs (lncRNAs) play crucial roles in sustaining the NF-κB pathway. However, the underlying mechanisms remain unclear. In this study, we identified the upregulated expressed lncRNA NBR2 in adipocyte-derived exosomes (AdEXO) and investigated its regulatory role in diabetic myocardial fibrosis. Hypothesis: We hypothesized that AdEXO-NBR2 promotes diabetic myocardial fibrosis through regulating the IκBα/NF-κB pathway. Methods: We examined the effect of exosomes from diabetic (db/db) mice-derived adipocytes on ANG-II-induced cardiac fibrosis and function in non-diabetic (C57BL/6J mice). In the invitro study, HG (33mmol/L)-stimulated AdEXO were cultured with adult human cardiac fibroblasts (aHCFs). Differentially expressed lncRNAs in AdEXO were screened using lncRNA sequencing. Results: Intramyocardial injection of diabetic AdEXO in the non-diabetic heart significantly exacerbated myocardial fibrosis, as evidenced by poorer cardiac function and enhancer collagen deposition. Whereas administration of a exosomes biogenesis inhibitor mitigated cardiac fibrosis in diabetic mice. We found lncRNA-NBR2 is a common molecule significantly increased in diabetic AdEXO and HG-stimulated non-diabetic AdEXO. After four weeks of ANG II infusion, EXO-db/dbWT-injected mice displayed fibrosis in the heart. However, interestingly, mice receiving NBR2-deficient db/db-EXO showed a decrease in cardiac fibrosis. Similarly, AdEXO-NBR2 promoted aHCFs proliferation and transformation capabilities in vitro. Mechanistically, NBR2 was loaded to AdEXO by directly interacting with heterogeneous nuclear ribonucleoprotein K (hnRNPK). Subsequently, AdEXO-NBR2 was internalized by aHCFs and epigenetically downregulated IκBα expression by recruitment of hnRNPK/SETDB1 and increasing the H3K9 trimethylation level in the IκBα promoter, ultimately activating the NF-κB pathway. Conclusions: Our findings highlight a novel epigenetic mechanism of AdEXO lncRNA-mediated diabetic cardiac fibrosis and identify NBR2 as a therapeutic target of DCM.

Download Full-text

Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

Cells ◽

10.3390/cells8080865 ◽

2019 ◽

Vol 8 (8) ◽

pp. 865 ◽

Cited By ~ 5

Author(s):

Tsai ◽

Lin ◽

Hang ◽

Chen

Keyword(s):

Myocardial Fibrosis ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Umbilical Vein ◽

Active Form ◽

Mesenchymal Transition ◽

Endothelial To Mesenchymal Transition ◽

Umbilical Vein Endothelial Cells

Doxorubicin (Dox) is an effective anti-neoplasm drug, but its cardiac toxicity limits its clinical use. Endothelial-to-mesenchymal transition (EndMT) has been found to be involved in the process of heart failure. It is unclear whether EndMT contributes to Dox-induced cardiomyopathy (DoIC). Calcitriol, an active form Vitamin D3, blocks the growth of cancer cells by inhibiting the Smad pathway. To investigate the effect of calcitriol via inhibiting EndMT in DoIC, C57BL/6 mice and endothelial-specific labeled mice were intraperitoneally administered Dox twice weekly for 4 weeks (32 mg/kg cumulative dose) and were subsequently treated with or without calcitriol for 12 weeks. Echocardiography revealed diastolic dysfunction at 13 weeks following the first Dox treatment, accompanied by increased myocardial fibrosis and up-regulated pro-fibrotic proteins. Calcitriol attenuated Dox-induced myocardial fibrosis, down-regulated pro-fibrotic proteins and improved diastolic function. Endothelial fate tracing revealed that EndMT-derived cells contributed to Dox-induced cardiac fibrosis. In vitro, human umbilical vein endothelial cells and mouse cardiac fibroblasts were treated with Transforming growth factor (TGF)-β with or without calcitriol. Morphological, immunofluorescence staining, and Western blot analyses revealed that TGF-β-induced EndMT and fibroblast-to-myofibroblast transition (FMT) were attenuated by calcitriol by the inhibition of the Smad2 pathway. Collectively, calcitriol attenuated DoIC through the inhibition of the EndMT and FMT processes.

Download Full-text

Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00685.2017 ◽

2018 ◽

Vol 315 (5) ◽

pp. H1127-H1136 ◽

Cited By ~ 19

Author(s):

Qing Qin ◽

Hemal Mehta ◽

Kelvin Yen ◽

Gerardo Navarrete ◽

Sebastian Brandhorst ◽

...

Keyword(s):

Oxidative Stress ◽

Growth Factor ◽

Myocardial Fibrosis ◽

Cardiac Fibrosis ◽

Biological Process ◽

Glycogen Synthase ◽

Myocardial Dysfunction ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3Β ◽

Aged Mice

Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin (HN) is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. The present study aimed to test the hypothesis that chronic supplementation of exogenous HN in middle-aged mice could prevent and reverse cardiac fibrosis and apoptosis in the aging heart. Female C57BL/6N mice at 18 mo of age received 14-mo intraperitoneal injections of vehicle (old group; n = 6) or HN analog (HNG; 4 mg/kg 2 times/wk, old + HNG group, n = 8) and were euthanized at 32 mo of age. C57BL/6N female mice (young group, n = 5) at 5 mo of age were used as young controls. HNG treatment significantly increased the ratio of cardiomyocytes to fibroblasts in aging hearts, as shown by the percentage of each cell type in randomly chosen fields after immunofluorescence staining. Furthermore, the increased collagen deposition in aged hearts was significantly reduced after HNG treatment, as indicated by picrosirius red staining. HNG treatment also reduced in aging mice cardiac fibroblast proliferation (5′-bromo-2-deoxyuridine staining) and attenuated transforming growth factor-β1, fibroblast growth factor-2, and matrix metalloproteinase-2 expression (immunohistochemistry or real-time PCR). Myocardial apoptosis was inhibited in HNG-treated aged mice (TUNEL staining). To decipher the pathway involved in the attenuation of the myocardial fibrosis by HNG, Western blot analysis was done and showed that HNG upregulated the Akt/glycogen synthase kinase -3β pathway in aged mice. Exogenous HNG treatment attenuated myocardial fibrosis and apoptosis in aged mice. The results of the present study suggest a role for the mitochondria-derived peptide HN in the cardioprotection associated with aging. NEW & NOTEWORTHY Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. Here, we demonstrate, for the first time, that exogenous humanin treatment attenuated myocardial fibrosis and apoptosis in aging mice. We also detected upregulated Akt/glycogen synthase kinase-3β pathway in humanin analog-treated mice, which might be the mechanism involved in the cardioprotective effect of humanin analog in aging mice.

Download Full-text

(Pro)renin receptor involves in myocardial fibrosis and oxidative stress in diabetic cardiomyopathy via the PRR–YAP pathway

Scientific Reports ◽

10.1038/s41598-021-82776-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shiran Yu ◽

Xuefei Dong ◽

Min Yang ◽

Qingtao Yu ◽

Jie Xiong ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Fibrosis ◽

Cardiac Fibroblasts ◽

Animal Experiments ◽

Specific Inhibitor ◽

Neonatal Rat ◽

Rnai Silencing ◽

The Impact

Abstract(Pro)renin receptor (PRR) and Yes-associated protein (YAP) play an important role in cardiovascular diseases. However, the role of PRR–YAP pathway in the pathogenesis of DCM is also not clear. We hypothesized that PRR–YAP pathway may promote pathological injuries in DCM by triggering redox. Wistar rats and neonatal rat cardiac fibroblasts were respectively used in vivo and in vitro studies. In order to observe the effects of PRR mediated YAP pathway on the pathogenesis of DCM, animal experiments were divided into 3 parts, including the evaluation the effects of PRR overexpression, PRR RNAi silencing and YAP RNAi silencing. Recombinant-adenoviruses-carried-PRR-gene (Ad-PRR), Ad-PRR-shRNA and lentivirus-carried-YAP-shRNA were constructed and the effects of PRR mediated YAP on the pathogenesis of DCM were evaluated. YAP specific inhibitor Verteporfin was also administrated in cardiac fibroblasts to explore the impact of PRR–YAP pathway on oxidative stress and myocardial fibrosis. The results displayed that PRR overexpression could enhance YAP expression but PRR RNAi silencing down-regulated its expression. Moreover, PRR overexpression could exacerbate oxidative stress and myocardial fibrosis in DCM, and these pathological changes could be rescued by YAP blockade. We concluded that PRR–YAP pathway plays a key role in the pathogenesis of DCM.

Download Full-text

Angelica sinensis Polysaccharide Alleviates Myocardial Fibrosis and Oxidative Stress in the Heart of Hypertensive Rats

Computational and Mathematical Methods in Medicine ◽

10.1155/2021/6710006 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Xiaolong Song ◽

Junhong Kong ◽

Jun Song ◽

Renyou Pan ◽

Lei Wang

Keyword(s):

Oxidative Stress ◽

Myocardial Fibrosis ◽

Smooth Muscle Actin ◽

Hypertensive Heart Disease ◽

Expression Level ◽

Angelica Sinensis ◽

Alpha Smooth Muscle Actin ◽

Systolic Volume ◽

End Diastolic Volume ◽

Shortening Rate

This research is aimed at studying the effect of Angelica sinensis polysaccharide (ASP) extracted from the Lixinshui prescription on cardiac disease induced by hypertension in rats. Rat models of cardiovascular disease were established, and the associated factors were measured. The data showed that ASP treatment increased the ejection fraction and short axis shortening rate, while decreasing the LV end-diastolic diameter, LV end-systolic diameter, LV end-diastolic volume, and LV end-systolic volume in HHD rats. ASP downregulated the expression level of TGF-β1, alpha-smooth muscle actin (α-SMA), collagen I, fibronectin, vimentin, Bax, cleaved caspase-9, and cleaved caspase-3 and upregulated the expression level of Bcl-2 in LV of HHD rats. Meanwhile, ASP increased the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the level of malondialdehyde (MDA), tissue endogenous hydrogen peroxide (H2O2), and reactive oxygen species (ROS). Our findings indicated that ASP could prevent hypertensive heart disease by inhibiting myocardial fibrosis, suppressing the myocardial apoptosis, and alleviating oxidative stress.

Download Full-text

Hydrogen Sulfide Attenuates Angiotensin II-Induced Cardiac Fibroblast Proliferation and Transverse Aortic Constriction-Induced Myocardial Fibrosis through Oxidative Stress Inhibition via Sirtuin 3

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9925771 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Lulu Liu ◽

Weiwei Gong ◽

Shuping Zhang ◽

Jieru Shen ◽

Yuqin Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Fibrosis ◽

Cardiac Fibroblasts ◽

Collagen I ◽

Ang Ii ◽

Transverse Aortic Constriction ◽

Sirtuin 3 ◽

Aortic Constriction ◽

Collagen Iii

Sirtuin 3 (SIRT3) is critical in mitochondrial function and oxidative stress. Our present study investigates whether hydrogen sulfide (H2S) attenuated myocardial fibrosis and explores the possible role of SIRT3 on the protective effects. Neonatal rat cardiac fibroblasts were pretreated with NaHS followed by angiotensin II (Ang II) stimulation. SIRT3 was knocked down with siRNA technology. SIRT3 promoter activity and expression, as well as mitochondrial function, were measured. Male wild-type (WT) and SIRT3 knockout (KO) mice were intraperitoneally injected with NaHS followed by transverse aortic constriction (TAC). Myocardium sections were stained with Sirius red. Hydroxyproline content, collagen I and collagen III, α-smooth muscle actin (α-SMA), and dynamin-related protein 1 (DRP1) expression were measured both in vitro and in vivo. We found that NaHS enhanced SIRT3 promoter activity and increased SIRT3 mRNA expression. NaHS inhibited cell proliferation and hydroxyproline secretion, decreased collagen I, collagen III, α-SMA, and DRP1 expression, alleviated oxidative stress, and improved mitochondrial respiration function and membrane potential in Ang II-stimulated cardiac fibroblasts, which were unavailable after SIRT3 was silenced. In vivo, NaHS reduced hydroxyproline content, ameliorated perivascular and interstitial collagen deposition, and inhibited collagen I, collagen III, and DRP1 expression in the myocardium of WT mice but not SIRT3 KO mice with TAC. Altogether, NaHS attenuated myocardial fibrosis through oxidative stress inhibition via a SIRT3-dependent manner.

Download Full-text