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Xinkeshu Improves Endothelial Function and Augments Reendothelialization Capacity in Coronary Artery Disease with
Jiapan Sun1,2, Meiling Zhou3, Guanghui Lv1
1Department of Geriatrics, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, China.
Insights
Xinkeshu (XKS) improves endothelial function and anxiety/depression symptoms in coronary artery disease (CAD) patients. It enhances endothelial progenitor cell repair capacity via the CXCR7/p38 signaling pathway, offering novel insights into treatment mechanisms.
Area of Science:
- Cardiovascular Medicine
- Neuroscience
- Pharmacology
Background:
- Endothelial dysfunction is central to coronary artery disease (CAD) and linked to anxiety/depression.
- Xinkeshu (XKS), a traditional Chinese medicine, is used for CAD and psychological conditions, but its mechanism on endothelial repair is unclear.
- CAD patients with anxiety/depression exhibit compromised endothelial function and repair capacity.
Purpose of the Study:
- To investigate the effects of Xinkeshu (XKS) on endothelial function and endothelial progenitor cell (EPC)-mediated reendothelialization in CAD patients with anxiety/depression.
- To elucidate the underlying molecular mechanisms involving CXCR7 and p38 signaling.
Main Methods:
- Compared endothelial function (flow-mediated dilation, FMD) and EPC-mediated reendothelialization capacity in healthy subjects, CAD patients without anxiety/depression, and CAD patients with anxiety/depression.
- Administered 1-month XKS treatment to CAD patients with anxiety/depression and assessed changes in FMD, anxiety/depression scores (GAD-7/PHQ-9), and EPC function.
- Utilized a mouse carotid artery injury model with XKS-incubated EPCs and molecular analyses (CXCR7, p38 phosphorylation, apoptosis) to explore mechanisms.
Main Results:
- CAD patients with anxiety/depression showed reduced FMD and EPC-mediated reendothelialization compared to controls.
- XKS treatment significantly improved FMD and reduced GAD-7/PHQ-9 scores in CAD patients with anxiety/depression.
- XKS enhanced EPC reendothelialization capacity and reduced apoptosis, associated with CXCR7 upregulation and p38 signaling inhibition.
- CXCR7 knockdown abolished XKS benefits, which were restored by p38 inhibition.
Conclusions:
- Xinkeshu (XKS) effectively improves endothelial function and alleviates anxiety/depression symptoms in CAD patients.
- XKS enhances endothelial repair by promoting EPC function through the CXCR7/p38/cleaved caspase-3 signaling pathway.
- These findings provide a mechanistic basis for XKS in managing endothelial homeostasis in CAD patients with comorbid anxiety/depression.
Abstract:
The disruption of endothelial homeostasis is the hallmark of coronary artery disease (CAD) and psychological disorders such as anxiety/depression. Xinkeshu (XKS), a traditional Chinese patent medicine, plays an essential role in CAD and psychological condition; however, the mechanisms underlying the effects of XKS on the endothelial function and endogenous endothelium-repair capacity in CAD patients with anxiety/depression remain elusive. In this study, endothelial function and endothelial progenitor cell- (EPC-) mediated reendothelialization capacity were compared among age-matched healthy subjects, CAD patients with or without anxiety/depression. Besides, CAD patients with anxiety/depression received 1-month XKS treatment. Anxiety/depression symptoms were evaluated by Generalized Anxiety Disorder 7-item (GAD-7)/Patient Health Questionnaire-9 (PHQ-9) score, endothelial function was tested by flow mediated dilation (FMD) measurement, and EPC-mediated reendothelialization capacity was evaluated by a carotid artery injury model in nude mouse (n = 6) with the injection of XKS-incubated EPCs from CAD patients with anxiety/depression. The results showed that FMD and EPC-mediated reendothelialization capacity of CAD patients with anxiety/depression were compromised compared to healthy subjects and CAD patients without anxiety/depression. After 1 month of XKS treatment, FMD increased from 4.29 ± 1.65 to 4.87 ± 1.58% (P < 0.05) in CAD patients with anxiety/depression, whereas it remained unchanged in the controls. Moreover, XKS decreased GAD-7 and PHQ-9 scores. Meanwhile, incubating XKS enhanced in vivo reendothelialization capacity and in vitro apoptosis of EPCs from CAD patients with anxiety/depression, which was associated with the upregulation of CXC-chemokine receptor 7 (CXCR7) and inhibition of phosphorylation of p38 signaling. CXCR7 knockdown abolished the beneficial effects of XKS, which was rescued by p38 inhibitor SB203580. Our data demonstrate for the first time that XKS improves endothelial function and enhances EPC-mediated reendothelialization through CXCR7/p38/cleaved casepase-3 signaling and provides novel insight into the detailed mechanism of XKS in maintaining endothelial homeostasis in CAD patients with anxiety/depression.
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