Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis

Yi, Chenlong; Wu, Weihua; Zheng, Dong; Peng, Guangying; Huang, Haoyue; Shen, Zhenya; Teng, Xiaochun

doi:10.1038/s41419-020-02737-x

Cited by 21 publications

(17 citation statements)

References 52 publications

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“…The formation of new blood vessels through angiogenesis is the key to wound healing. Insufficient angiogenesis not only leads to reduced blood flow and oxygen but also restricts the entry of inflammation cells including macrophages into the wound, leading to delayed wound healing [ 26 ]. In the wound treated using SXYH ointment, the formation of new blood vessels was more obvious than in the control group.…”

Section: Resultsmentioning

confidence: 99%

Effects of the Chinese Herb Medicine Formula “She-Xiang-Yu-Hong” Ointment on Wound Healing Promotion in Diabetic Mice

Liu

Shi-hui

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Wound healing in diabetic patients is a difficult problem to be solved at present. In addition, patients with diabetes have an increased risk of postoperative wound complications. “She-Xiang-Yu-Hong” (SXYH) ointment is a type of traditional Chinese medicine (TCM) compound used to treat wounds. Over the past few years, SXYH has been applied in the Affiliated Hospital of Chengdu University of TCM (Chengdu, China) for the treatment of diabetic foot infections and bedsores, whereas there has been rare research on the effect of SXYH ointment on wound healing. In this study, SXYH ointment was first applied to streptozotocin (STZ)-triggered diabetic ICR mice (4–6 weeks, 20 ± 2 g) to observe the accelerated wound healing and the shortened wound healing period. As indicated by the histology and biochemistry analyses of skin biopsies, the wounds treated using SXYH ointment showed an increase in the granulation tissue. Moreover, SXYH also modulated the inflammation response by regulating affinity proinflammatory cytokines release (e.g., IL-6 and TNF-α). Furthermore, SXYH ointment obviously improved collagen fiber deposition and tissue on the wound surface. On the whole, this study indicated that SXYH ointment could accelerate wound healing, promote blood vessel formation, and suppress inflammations. Thus, the clinical potential of SXYH ointment was demonstrated in the treatment of diabetes and refractory wounds.

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Section: Resultsmentioning

confidence: 99%

Effects of the Chinese Herb Medicine Formula “She-Xiang-Yu-Hong” Ointment on Wound Healing Promotion in Diabetic Mice

Liu

Shi-hui

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…The initial inflammation is a key phase in the wound healing process, which partially triggers the angiogenic response by producing high levels of VEGF [21,22]. Macrophages have a controversial role in the wound healing process: they can influence the outcome either towards a minimum scar tissue or to an impaired healing wound, as a function of the balance between the occurrence of inflammatory (M1) and reparatory (M2) macrophage phenotype [23,24].…”

Section: Discussionmentioning

confidence: 99%

Human Mesenchymal Stromal Cell-Derived Exosomes Promote In Vitro Wound Healing by Modulating the Biological Properties of Skin Keratinocytes and Fibroblasts and Stimulating Angiogenesis

Ţuţuianu¹,

Rosca²,

Iacomi³

et al. 2021

IJMS

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Bone marrow-derived mesenchymal stromal cells (MSCs) are major players in regenerative therapies for wound healing via their paracrine activity, mediated partially by exosomes. Our purpose was to test if MSC-derived exosomes could accelerate wound healing by enhancing the biological properties of the main cell types involved in the key phases of this process. Thus, the effects of exosomes on (i) macrophage activation, (ii) angiogenesis, (iii) keratinocytes and dermal fibroblasts proliferation and migration, and (iv) the capacity of myofibroblasts to regulate the turnover of the extracellular matrix were evaluated. The results showed that, although exosomes did not exhibit anti-inflammatory properties, they stimulated angiogenesis. Exposure of keratinocytes and dermal (myo)fibroblasts to exosomes enhanced their proliferation and migratory capacity. Additionally, exosomes prevented the upregulation of gene expression for type I and III collagen, α-smooth muscle actin, and MMP2 and 14, and they increased MMP13 expression during the fibroblast–myofibroblast transition. The regenerative properties of exosomes were validated using a wound healing skin organotypic model, which exhibited full re-epithelialization upon exosomes exposure. In summary, these data indicate that exosomes enhance the biological properties of keratinocytes, fibroblasts, and endothelial cells, thus providing a reliable therapeutic tool for skin regeneration.

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“…It is generally known that autophagy can be pharmacologically induced by inhibiting mTOR with rapamycin, whereas 3-MA inhibits autophagy by targeting the class III PI3K involved in autophagosome formation [55]. IL-1β, IL-6, and ICAM-1 are important proinflammatory molecules, which play crucial roles in the preliminary inflammatory response and endothelial dysfunction [56]. Our results showed that rapamycin could partially reverse the upregulation of IL-1β, IL-6, and ICAM-1 induced by oxLDL/β2GPI/anti-β2GPI complex, while the 3-MA treatment resulted in increased expressions of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Impaired Autophagy Induced by oxLDL/β2GPI/anti‐β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Endothelial cell dysfunction plays a fundamental role in the pathogenesis of atherosclerosis (AS), and endothelial autophagy has protective effects on the development of AS. Our previous study had shown that oxidized low-density lipoprotein/β2-glycoprotein I/anti-β2-glycoprotein I antibody (oxLDL/β2GPI/anti-β2GPI) complex could promote the expressions of inflammatory cytokines and enhance the adhesion of leukocytes to endothelial cells. In the present study, we aimed to assess the effects of oxLDL/β2GPI/anti-β2GPI complex on endothelial autophagy and explore the associated potential mechanisms. Human umbilical vein endothelial cells (HUVECs) and mouse brain endothelial cell line (bEnd.3) were used as models of the vascular endothelial cells. Autophagy was evaluated by examining the expressions of autophagic proteins using western blotting analysis, autophagosome accumulation using transmission electron microscopy, and RFP-GFP-LC3 adenoviral transfection and autophagic flux using lysosome inhibitor chloroquine. The expressions of phospho-PI3K, phospho-AKT, phospho-mTOR, and phospho-eNOS were determined by western blotting analysis. 3-Methyladenine (3-MA) and rapamycin were used to determine the role of autophagy in oxLDL/β2GPI/anti-β2GPI complex-induced endothelial cell dysfunction. We showed that oxLDL/β2GPI/anti-β2GPI complex suppressed the autophagy, evidenced by an increase in p62 protein, a decrease in LC3-II and Beclin1, and a reduction of autophagosome generation in endothelial cells. Moreover, inhibition of autophagy was associated with PI3K/AKT/mTOR and eNOS signaling pathways. Rapamycin attenuated oxLDL/β2GPI/anti-β2GPI complex-induced endothelial inflammation, oxidative stress, and apoptosis, whereas 3-MA alone induced the endothelial injury. Our results suggested that oxLDL/β2GPI/anti-β2GPI complex inhibited endothelial autophagy via PI3K/AKT/mTOR and eNOS signaling pathways and further contributed to endothelial cell dysfunction. Collectively, our findings provided a novel mechanism for vascular endothelial injury in AS patients with an antiphospholipid syndrome (APS) background.

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Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis

Cited by 21 publications

References 52 publications

Effects of the Chinese Herb Medicine Formula “She-Xiang-Yu-Hong” Ointment on Wound Healing Promotion in Diabetic Mice

Effects of the Chinese Herb Medicine Formula “She-Xiang-Yu-Hong” Ointment on Wound Healing Promotion in Diabetic Mice

Human Mesenchymal Stromal Cell-Derived Exosomes Promote In Vitro Wound Healing by Modulating the Biological Properties of Skin Keratinocytes and Fibroblasts and Stimulating Angiogenesis

Impaired Autophagy Induced by oxLDL/β2GPI/anti‐β2GPI Complex through PI3K/AKT/mTOR and eNOS Signaling Pathways Contributes to Endothelial Cell Dysfunction

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