Bradykinin protects cardiac c‐kit positive cells from high‐glucose‐induced senescence through B2 receptor signaling pathway

Fu, Cong; Cao, Yuhan; Li, Bing; Xu, Rongfeng; Sun, Yuning; Yao, Yuyu

doi:10.1002/jcb.29039

Cited by 8 publications

(6 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some researchers have suggested that the key role of mTOR is to adjust the balance of pro-inflammatory and anti-inflammatory responses to further regulate the immune system [35]. In addition, mTOR signal pathway was found to promote cell proliferation; strongly indicating that activation of mTOR may be beneficial in stress or inflammatory conditions [25,36]. In the present research, we found that ticagrelor promoted the activation of mTOR via phosphorylated of Akt and further lead to apoptosis of cardiomyocytes.…”

supporting

confidence: 63%

See 1 more Smart Citation

Ticagrelor alleviates sepsis-induced myocardial injury via an adenosine-dependent pathway in a mouse sepsis model

Tang¹,

Xu³

et al. 2020

CIM

Self Cite

View full text Add to dashboard Cite

Purpose: The purpose of this study was to determine whether ticagrelor, a classic anti-platelet drug, has a therapeutic effect on sepsis-induced myocardial injury. Methods: The C57BL6J mice received oral ticagrelor (10, 25 and 50 mg/kg) for seven days after which cecum ligation and puncture (CLP) were performed. An adenosine-receptor antagonist (CGS15943) was administered two hours before CLP. After 24 h, cardiac function was measured using cardiac echocardiography, then the heart and blood were collected. Hematoxylin and eosin (HE) staining and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL staining) were used to observe pathological changes and cardiomyocyte apoptosis. Plasma concentration of TNF-α, IL-6 and adenosine and myocardial tissue levels of TNF-α and IL-6 were determined. Survival analysis was performed. Western blot was used to determine the expression of a signalling protein in the myocardial tissue. Results: The HE and TUNEL staining showed less inflammatory cell infiltration and less cardiomyocyte apoptosis in the ticagrelor group. Cardiac echocardiography showed preserved heart function in the ticagrelor group. Plasma TNF-α, IL-6 and relative expression of TNF-α and IL-6 in myocardial tissue were significantly lower in the ticagrelor group. Plasma adenosine levels were significantly higher in the ticagrelor group. Adenosine-receptor antagonists significantly blocked the protective effect of ticagrelor. Ticagrelor reduced the mortality of sepsis mice, and this reduction was blocked by the adenosine-receptor antagonist. Western blot showed that ticagrelor activated the phosphorylation of AKT and mTOR. Adenosine-receptor antagonists inhibited the activation of AKT and mTOR. Conclusion: The protective effect of ticagrelor was dependent on adenosine-receptor activation, with downstream upregulation of phosphorylation of AKT and mTOR.

show abstract

supporting

confidence: 63%

“…The protein, PI3K, is a classic signal molecule that regulates cell proliferation, senescence and apoptosis [25]. Adenosine can efficiently activate the PI3K signal pathway that enables this protecting effect [26,27].…”

Section: Discussionmentioning

confidence: 99%

Ticagrelor alleviates sepsis-induced myocardial injury via an adenosine-dependent pathway in a mouse sepsis model

Tang¹,

Xu³

et al. 2020

CIM

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the present study, in vitro, we found that BK exerts a formidable anti-apoptotic effect on cultured CPCs by inhibiting pro-apoptosis protein Bax and cleaved caspase 3 and increases the expression of antiapoptosis protein, Bcl-2. These protective effects of BK in vitro are consistent with the findings of the abovementioned in vitro studies on the effect of BK on highglucose-induced senescence of CPCs [10], oxidative stress-induced senescence of EPCs [33], and NPCs [34].…”

Section: Discussionsupporting

confidence: 90%

“…Interestingly, several independent research groups reported the potential protective role of BK in stem/progenitor cells, including endothelial progenitor cells (EPCs), neural progenitor cells (NPCs), and CPCs. In vitro, BK was applied to protect CPCs from high-glucose-induced senescence [10], and EPCs from oxidative stress-induced senescence [33], as well as enhance neuron-generating division of NPCs [34]. In addition, two other studies determined the protective effect of BK on EPCs in vivo; one of them showed that BK-treated EPCs showed robust cell antiapoptosis, reduction in infarct size, and significant improvement in cardiac function [35], and the other one showed that BK preconditioning increased EPC migration, tube formation, and neovascularization and improved cardiac function following transplantation [36].…”

Section: Discussionmentioning

confidence: 99%

“…Bradykinin (BK) is a classic endogenous vasoactive peptide that protects cells against senescence or other damage by acting as a B2 receptor [9,10]. Our previous findings demonstrated that BK-mediated B2R activation promotes cell cycle progression and migration in hCPCs by regulating Ca 2+ via IP3R3 and SOCE channels as well as activating PLC, PKC, pERK1/2, pAkt, and cyclin D1 signaling pathway [11,12].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pretreatment of cardiac progenitor cells with bradykinin attenuates H2O2-induced cell apoptosis and improves cardiac function in rats by regulating autophagy

Zhou

Qiang

et al. 2021

Stem Cell Res Ther

View full text Add to dashboard Cite

Background Previous studies have demonstrated that human cardiac c-Kit+ progenitor cells (hCPCs) can effectively improve ischemic heart disease. However, the major challenge in applying hCPCs to clinical therapy is the low survival rate of graft hCPCs in the host heart, which limited the benefit of transplanted hCPCs. Bradykinin (BK) is a principal active agent of the tissue kinin-kallikrein system. Our previous studies have highlighted that BK mediated the growth and migration of CPCs by regulating Ca2+ influx. However, the protective effect of BK on CPCs, improvement in the survival rate of BK-pretreated hCPCs in the infarcted heart, and the related mechanism remain elusive. Methods HCPCs were treated with H2O2 to induce cell apoptosis and autophagy, and different concentration of BK was applied to rescue the H2O2-induced injury detected by MTT assay, TUNEL staining, flow cytometry, western blotting, and mitoSOX assays. The role of autophagy in the anti-apoptotic effect of BK was chemically activated or inhibited using the autophagy inducer, rapamycin, or the inhibitor, 3-methyladenine (3-MA). To explore the protective effect of BK on hCPCs, 3-MA or BK-pretreated hCPCs were transplanted into the myocardial infarcted rats. An echocardiogram was used to determine cardiac function, H&E and Masson staining were employed to assess pathological characteristics, HLA gene expression was quantified by qRT-PCR, and immunostaining was applied to examine neovascularization using confocal microscopy. Results The in vitro results showed that BK suppressed H2O2-induced hCPCs apoptosis and ROS production in a concentration-dependent manner by promoting pAkt and Bcl-2 expression and reducing cleaved caspase 3 and Bax expression. Moreover, BK restrained the H2O2-induced cell autophagy by decreasing LC3II/I, Beclin1, and ATG5 expression and increasing P62 expression. In the in vivo experiment, the transplanted BK- or 3-MA-treated hCPCs were found to be more effectively improved cardiac function by decreasing cardiomyocyte apoptosis, inflammatory infiltration, and myocardial fibrosis, and promoting neovascularization in the infarcted heart, compared to untreated-hCPCs or c-kit- cardiomyocytes (CPC- cells). Conclusions Our present study established a new method to rescue transplanted hCPCs in the infarcted cardiac area via regulating cell apoptosis and autophagy of hCPCs by pretreatment with BK, providing a new therapeutic option for heart failure.

show abstract

Development of a multigram synthesis of the bradykinin receptor 2 agonist FR‐190997 and analogs thereof

Vachlioti

Ferikoglou

Georgiou

et al. 2023

Archiv der Pharmazie

View full text Add to dashboard Cite

Using Fujisawa's B2R agonist FR-190997, we recently demonstrated for the first time that agonism at the bradykinin receptor type 2 (B2R) produces substantial antiproliferative effects. FR-190997 elicited an EC 50 of 80 nM in the triple-negative breast cancer cell line MDA-MB-231, a much superior performance to that exhibited by most approved breast cancer drugs. Consequently, we initiated a program aiming primarily at synthesizing adequate quantities of FR-190997 to support further in vitro and in vivo studies toward its repurposing for various cancers and, in parallel, enable the generation of novel FR-190997 analogs for an SAR study. Prerequisite for this endeavor was to address the synthetic challenges associated with the FR-190997 scaffold, which the Fujisawa chemists had constructed in 20 steps, 13 of which required chromatographic purification. We succeeded in developing a 17-step synthesis amenable to late-stage diversification that eliminated all chromatography and enabled access to multigram quantities of FR-190997 and novel derivatives thereof, supporting further anticancer research based on B2R agonists.

show abstract

Bradykinin protects cardiac c‐kit positive cells from high‐glucose‐induced senescence through B2 receptor signaling pathway

Cited by 8 publications

References 34 publications

Ticagrelor alleviates sepsis-induced myocardial injury via an adenosine-dependent pathway in a mouse sepsis model

Ticagrelor alleviates sepsis-induced myocardial injury via an adenosine-dependent pathway in a mouse sepsis model

Pretreatment of cardiac progenitor cells with bradykinin attenuates H2O2-induced cell apoptosis and improves cardiac function in rats by regulating autophagy

Development of a multigram synthesis of the bradykinin receptor 2 agonist FR‐190997 and analogs thereof

Contact Info

Product

Resources

About