Activation of endothelial NO synthase by a xanthine derivative ameliorates hypoxia-induced apoptosis in endothelial progenitor cells

Wu, Jiunn‐Ren; Hsu, Jong‐Hau; Dai, Zen‐Kong; Wu, Bin–Nan; Chen, Ing‐Jun; Liou, Shu-Fen; Yeh, Jwu‐Lai

doi:10.1111/jphp.12555

Cited by 14 publications

(12 citation statements)

References 47 publications

(65 reference statements)

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“…In addition, baicalin suppressed oxidative activity in the endplate chondrocytes induced by H 2 O 2 , via effectively reducing levels of MDA, increasing levels of SOD, and elevating NO activities (5,9,22). eNOS, an enzyme which activates the expression of NO (23)(24)(25), was also shown to be increased following pretreatment with baicalin, which suggested that baicalin also inhibited the apoptosis through upregulating the expression of eNOS.…”

Section: Discussionmentioning

confidence: 91%

Baicalin prevents the apoptosis of endplate chondrocytes by inhibiting the oxidative stress induced by H2O2

Pan

Chen

et al. 2017

Molecular Medicine Reports

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Osteoarthritis (OA) is a degenerative disease of articular cartilage. The pathogenesis of OA remains to be fully elucidated, and several studies have found that oxidative stress is important in its pathogenesis. Baicalin is well known and has already been investigated for its role of inhibiting the oxidative stress pathway. Thus, the present study aimed to investigate the role of baicalin on the inhibition of oxidative stress in endplate chondrocytes induced by hydrogen peroxide (H2O2). Following treatment of endplate chondrocytes with different doses of H2O2 with or without baicalin for different incubation durations, a CCK‑8 assay and Annexin V/PI staining were used to measure the cell proliferation and apoptotic rates to identify the optimal experimental conditions. Subsequently, for examining the effects and underlying mechanism of baicalin on oxidative stress, the protein expression levels of cleaved‑poly (ADP‑ribose) polymerase (PARP), B‑cell lymphoma‑2‑associated X protein (Bax) and pro‑caspase‑3 were analyzed using western blot analysis, intracellular anti‑oxidant activities, including those of malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO), were quantified, and the levels of endothelial nitric oxide synthase (eNOS) were examined using reverse transcription‑polymerase chain reaction analysis. The results revealed that the oxidative stress of endplate chondrocytes induced by 0.5 mM H2O2 for 4 h were the most appropriate conditions for experiments, and pretreatment with 100 µmol/l baicalin for 1 h effectively reversed the effect of H2O2 on the endplate chondrocytes. In addition, Annexin V/PI staining demonstrated that the cell death induced by H2O2 was apoptotic, and baicalin reversed the apoptosis induced by oxidative stress. H2O2 activated PARP cleavage, and the expression of Bax and pro‑caspase‑3; however, baicalin inhibited the expression of these apoptotic signaling indicators. Baicalin also reduced the levels of MDA, and increased the levels of SOD and NO. Baicalin also significantly elevated the mRNA levels of eNOS in endplate chondrocytes. Therefore, the results of the present study showed that baicalin significantly inhibited the oxidative stress in endplate chondrocytes induced by H2O2, and decreased cell apoptosis.

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Section: Discussionmentioning

confidence: 91%

Baicalin prevents the apoptosis of endplate chondrocytes by inhibiting the oxidative stress induced by H2O2

Pan

Chen

et al. 2017

Molecular Medicine Reports

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“…Additionally, TRPC3 could provide an additional source of Ca 2+ for eNOS stimulation, as recently shown in porcine coronary artery endothelial cells (PCAECs) (Huang et al, ). As anticipated above, besides stimulating EPC egression from BM, NO controls EPC‐dependent angiogenesis and vascular remodeling by promoting proliferation and migration and inhibiting apoptosis (Bai et al, ; Lu et al, ; Ozuyaman et al, ; Wu et al, ; Zuccolo, Bottino, et al, ). The up‐regulation of NO synthesis by exogenously expressed TRPC3 could be even more therapeutically relevant in ECFCs.…”

Section: Introductionmentioning

confidence: 93%

TRPC3‐mediated Ca²⁺ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

Moccia

Lucariello

Guerra³

2017

Journal Cellular Physiology

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Endothelial progenitor cells (EPCs) are a sub-population of bone marrow-derived mononuclear cells that are released in circulation to restore damaged endothelium during its physiological turnover or rescue blood perfusion after an ischemic insult. Additionally, they may be mobilized from perivascular niches located within larger arteries' wall in response to hypoxic conditions. For this reason, EPCs have been regarded as an effective tool to promote revascularization and functional recovery of ischemic hearts, but clinical application failed to exploit the full potential of patients-derived cells. Indeed, the frequency and biological activity of EPCs are compromised in aging individuals or in subjects suffering from severe cardiovascular risk factors. Rejuvenating the reparative phenotype of autologous EPCs through a gene transfer approach has, therefore, been put forward as an alternative approach to enhance their therapeutic potential in cardiovascular patients. An increase in intracellular Ca concentration constitutes a pivotal signal for the activation of the so-called endothelial colony forming cells (ECFCs), the only known truly endothelial EPC subset. Studies from our group showed that the Ca toolkit differs between peripheral blood- and umbilical cord blood (UCB)-derived ECFCs. In the present article, we first discuss how VEGF uses repetitive Ca spikes to regulate angiogenesis in ECFCs and outline how VEGF-induced intracellular Ca oscillations differ between the two ECFC subtypes. We then hypothesize about the possibility to rejuvenate the biological activity of autologous ECFCs by transfecting the cell with the Ca -permeable channel Transient Receptor Potential Canonical 3, which selectively drives the Ca response to VEGF in UCB-derived ECFCs.

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“…Of note, endogenous nitric oxide (NO), as a paracrine pro-angiogenic signaling molecule, is primarily synthesized by endothelial nitric oxide synthase (eNOS) and released from EPCs or mature endothelial cells during neovascularization [15,16]. It is well known that NO could improve EPCs' and endothelial cells' migration, angiogenesis, and resistance to apoptosis [17][18][19], and therefore, NO release contributes to the paracrine properties of EPCs during tissue neovascularization.…”

Section: Introductionmentioning

confidence: 99%

Conditioned media from endothelial progenitor cells cultured in simulated microgravity promote angiogenesis and bone fracture healing

Kong

Wang

et al. 2021

Stem Cell Res Ther

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Background Paracrine signaling from endothelial progenitor cells (EPCs) is beneficial for angiogenesis and thus promotes tissue regeneration. Microgravity (MG) environment is found to facilitate the functional potentials of various stem or progenitor cells. The present study aimed to elucidate the effects of MG on pro-angiogenic properties and fracture repair capacities of conditioned media (CM) from EPCs. Methods Human peripheral blood-derived EPCs were cultured under MG or normal gravity (NG) followed by analysis for angiogenic gene expression. Furthermore, the serum-free CM under MG (MG-CM) or NG (NG-CM) were collected, and their pro-angiogenic properties were examined in human umbilical vein endothelial cells (HUVECs). In order to investigate the effects of MG-CM on fracture healing, they were injected into the fracture gaps of rat models, and radiography, histology, and mechanical test were performed to evaluate neovascularization and fracture healing outcomes. Results MG upregulated the expression of hypoxia-induced factor-1α (HIF-1α) and endothelial nitric oxide synthase (eNOS) and promoted NO release. Comparing to NG-CM, MG-CM significantly facilitated the proliferation, migration, and angiogenesis of HUVECs through NO-induced activation of FAK/Erk1/2-MAPK signaling pathway. In addition, MG-CM were verified to improve angiogenic activities in fracture area in a rat tibial fracture model, accelerate fracture healing, and well restore the biomechanical properties of fracture bone superior to NG-CM. Conclusion These findings provided insight into the use of MG bioreactor to enhance the angiogenic properties of EPCs’ paracrine signals via HIF-1α/eNOS/NO axis, and the administration of MG-CM favored bone fracture repair. Graphical abstract

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Activation of endothelial NO synthase by a xanthine derivative ameliorates hypoxia-induced apoptosis in endothelial progenitor cells

Abstract: KMUP-1 inhibited hypoxia-induced dysfunction and apoptosis in EPCs, which may be mediated through suppressing oxidative stress, upregulating eNOS and downregulating the caspase-3 signalling pathway.

Cited by 14 publications

References 47 publications

Baicalin prevents the apoptosis of endplate chondrocytes by inhibiting the oxidative stress induced by H2O2

Baicalin prevents the apoptosis of endplate chondrocytes by inhibiting the oxidative stress induced by H2O2

TRPC3‐mediated Ca²⁺ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

Conditioned media from endothelial progenitor cells cultured in simulated microgravity promote angiogenesis and bone fracture healing

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Activation of endothelial NO synthase by a xanthine derivative ameliorates hypoxia-induced apoptosis in endothelial progenitor cells

Abstract: KMUP-1 inhibited hypoxia-induced dysfunction and apoptosis in EPCs, which may be mediated through suppressing oxidative stress, upregulating eNOS and downregulating the caspase-3 signalling pathway.

Cited by 14 publications

References 47 publications

Baicalin prevents the apoptosis of endplate chondrocytes by inhibiting the oxidative stress induced by H2O2

Baicalin prevents the apoptosis of endplate chondrocytes by inhibiting the oxidative stress induced by H2O2

TRPC3‐mediated Ca2+ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

Conditioned media from endothelial progenitor cells cultured in simulated microgravity promote angiogenesis and bone fracture healing

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TRPC3‐mediated Ca²⁺ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells