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The present study suggests that Creatine supplementation has anti-inflammatory activities against endothelial cells.
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PubMed
Abstract:
1 Creatine (CR) supplementation augments muscle strength in skeletal muscle cells by increasing intracellular energy pools. However, the effect of CR supplementation on endothelial cells remains to be clarified. 2 In this study, we investigated whether CR supplementation had any anti-inflammatory activity against human pulmonary endothelial cells in culture. 3 We confirmed that supplementation with 0.5 mM CR significantly increased both intracellular CR and phosphocreatine (PC) through a CR transporter while keeping intracellular ATP levels constant independent of CR supplementation and a CR transporter antagonist. 4 In the assay system of endothelial permeability, supplementation with 5 mM CR significantly suppressed the endothelial permeability induced by serotonin and H(2)O(2). 5 In cell adhesion experiments, supplementation with 5 mM CR significantly suppressed neutrophil adhesion to endothelial cells. 6 In the measurement of adhesion molecules, CR supplementation with more than 0.5 mM CR significantly inhibited the expressions of ICAM-1 and E-selectin on endothelial cells, and the inhibition was significantly suppressed by an adenosine A(2A) receptor antagonist. 7 The present study suggests that CR supplementation has anti-inflammatory activities against endothelial cells.
Abstract:
1 Creatine (CR) supplementation augments muscle strength in skeletal muscle cells by increasing intracellular energy pools. However, the effect of CR supplementation on endothelial cells remains to be clarified. 2 In this study, we investigated whether CR supplementation had any anti-inflammatory activity against human pulmonary endothelial cells in culture. 3 We confirmed that supplementation with 0.5 mM CR significantly increased both intracellular CR and phosphocreatine (PC) through a CR transporter while keeping intracellular ATP levels constant independent of CR supplementation and a CR transporter antagonist. 4 In the assay system of endothelial permeability, supplementation with 5 mM CR significantly suppressed the endothelial permeability induced by serotonin and H(2)O(2). 5 In cell adhesion experiments, supplementation with 5 mM CR significantly suppressed neutrophil adhesion to endothelial cells. 6 In the measurement of adhesion molecules, CR supplementation with more than 0.5 mM CR significantly inhibited the expressions of ICAM-1 and E-selectin on endothelial cells, and the inhibition was significantly suppressed by an adenosine A(2A) receptor antagonist. 7 The present study suggests that CR supplementation has anti-inflammatory activities against endothelial cells.
PubMed
In this study, we examined the effect of CR supplementation on endothelial cell parameters in vitro, and found that it inhibited endothelial permeability, neutrophil adhesion to endothelial cells, and adhesion molecule expression. It is suggested that CR supplementation may serve as a suppressor of inflammation at the endothelial cell level.
It is highly possible that the PC energy system is active in endothelial cells, based on the fact that a few reports demonstrated that endothelial cells of umbilical veins contained PC (Loike et al., 1992; Windischbauer et al., 1994). However, those previous reports did not show intracellular CR levels or the role of CR in endothelial cells. We first measured the intracellular CR to assess whether CR might exist inside cultured endothelial cells. We demonstrated a significant level of intracellular CR, and found that CR supplementation further increased it through a CR transporter.
Endothelial cells were also found to contain a sufficient amount of high-energy phosphate compounds. The contents of PC and ATP were 44 and 30 nmol mg protein−1, respectively, which are three to five times higher than their contents in umbilical endothelial cells (Loike et al., 1992). The reason for the difference is unknown, but it might depend upon localization or functions of endothelial cells. On the other hand, muscle cells have been reported to contain more high-energy phosphate compounds than endothelial cells do. ATP is a requisite for muscle cells to constrict. In addition, muscle cells are equipped with the PC energy system to prevent ATP depletion. Such evidence suggests that the PC energy system is active in endothelial cells, although its role is unclear.
Extracellular CR is tightly linked to intracellular energy pools in myocardial and skeletal muscle cells (Seraydarian and Artaza, 1976). On the other hand, we demonstrated that CR supplementation stimulates endothelial cells to generate intracellular PC by CR uptake through a CR transporter. These findings, taken together, suggest that most cells, including muscle and endothelial cells, might be equipped with the mechanism by which CR supplementation induces intracellular energy pools. However, the capacity of PC biosynthesis is likely to differ among cell types. CR supplementation was found to increase the PC concentration in endothelial cells to 74 nmol mg protein−1, which value was comparable to that in skeletal muscle cells (Seraydarian and Artaza, 1976). However, PC concentration in myocardial cells has been reported to be 107 nmol mg protein−1 after CR supplementation (Seraydarian and Artaza, 1976). In contrast with the level of PC, that of intracellular ATP was found to be unsusceptible to CR supplementation or a CR transporter antagonist. Given that PC can provide ATP immediately on demand, these findings suggest that CR supplementation increases intracellular energy pools in endothelial cells through the PC energy system.
We hypothesized that CR supplementation might influence endothelial functions by augmenting intracellular energy pools, and examined the effect of CR supplementation on endothelial permeability, neutrophil adhesion to endothelial cells, and the expression of adhesion molecules. Supplementation with 5 mm CR significantly inhibited endothelial permeability independent of the type of stimulus used. In addition, CR supplementation was found to inhibit the adhesion of neutrophils to endothelial cells. This inhibition can be partly explained by adhesion molecule suppression; CR supplementation suppressed both ICAM-1 and E-selectin expressions on endothelial cells in a dose-dependent manner.
There is a possibility that ATP released from endothelial cells may be involved in the CR supplementation-induced inhibition of endothelial permeability, neutrophil adhesion to endothelial cells, and the expression of adhesion molecules. It has been reported that endothelial cells release ATP during acute inflammation or shear stress (Bodin & Burnstock, 1998;2001). Like endothelial cells, epithelial cells have also been reported to release ATP (Knight et al., 2002).
Furthermore, adenosine has been shown to have an inhibitory activity against endothelial permeability and adhesion molecule expression through the adenosine A2A receptor (Haselton et al., 1993; Okusa et al., 2000; McPherson et al., 2001). We also demonstrated that the adenosine A2A receptor antagonist suppressed the CR supplementation-mediated inhibition of adhesion molecule expressions. Taken together, CR supplementation may enhance ATP release from endothelial cells by increasing PC storage, resulting in anti-inflammatory activities through the adenosine A2A receptor against endothelial cells.
In summary, CR supplementation inhibited endothelial permeability, neutrophil adhesion, and adhesion molecule expression on cultured endothelial cells. Findings in the present study suggest that CR supplementation might inhibit endothelial cell-mediated inflammation by increasing intracellular PC contents.
In this study, we examined the effect of CR supplementation on endothelial cell parameters in vitro, and found that it inhibited endothelial permeability, neutrophil adhesion to endothelial cells, and adhesion molecule expression. It is suggested that CR supplementation may serve as a suppressor of inflammation at the endothelial cell level.
It is highly possible that the PC energy system is active in endothelial cells, based on the fact that a few reports demonstrated that endothelial cells of umbilical veins contained PC (Loike et al., 1992; Windischbauer et al., 1994). However, those previous reports did not show intracellular CR levels or the role of CR in endothelial cells. We first measured the intracellular CR to assess whether CR might exist inside cultured endothelial cells. We demonstrated a significant level of intracellular CR, and found that CR supplementation further increased it through a CR transporter.
Endothelial cells were also found to contain a sufficient amount of high-energy phosphate compounds. The contents of PC and ATP were 44 and 30 nmol mg protein−1, respectively, which are three to five times higher than their contents in umbilical endothelial cells (Loike et al., 1992). The reason for the difference is unknown, but it might depend upon localization or functions of endothelial cells. On the other hand, muscle cells have been reported to contain more high-energy phosphate compounds than endothelial cells do. ATP is a requisite for muscle cells to constrict. In addition, muscle cells are equipped with the PC energy system to prevent ATP depletion. Such evidence suggests that the PC energy system is active in endothelial cells, although its role is unclear.
Extracellular CR is tightly linked to intracellular energy pools in myocardial and skeletal muscle cells (Seraydarian and Artaza, 1976). On the other hand, we demonstrated that CR supplementation stimulates endothelial cells to generate intracellular PC by CR uptake through a CR transporter. These findings, taken together, suggest that most cells, including muscle and endothelial cells, might be equipped with the mechanism by which CR supplementation induces intracellular energy pools. However, the capacity of PC biosynthesis is likely to differ among cell types. CR supplementation was found to increase the PC concentration in endothelial cells to 74 nmol mg protein−1, which value was comparable to that in skeletal muscle cells (Seraydarian and Artaza, 1976). However, PC concentration in myocardial cells has been reported to be 107 nmol mg protein−1 after CR supplementation (Seraydarian and Artaza, 1976). In contrast with the level of PC, that of intracellular ATP was found to be unsusceptible to CR supplementation or a CR transporter antagonist. Given that PC can provide ATP immediately on demand, these findings suggest that CR supplementation increases intracellular energy pools in endothelial cells through the PC energy system.
We hypothesized that CR supplementation might influence endothelial functions by augmenting intracellular energy pools, and examined the effect of CR supplementation on endothelial permeability, neutrophil adhesion to endothelial cells, and the expression of adhesion molecules. Supplementation with 5 mm CR significantly inhibited endothelial permeability independent of the type of stimulus used. In addition, CR supplementation was found to inhibit the adhesion of neutrophils to endothelial cells. This inhibition can be partly explained by adhesion molecule suppression; CR supplementation suppressed both ICAM-1 and E-selectin expressions on endothelial cells in a dose-dependent manner.
There is a possibility that ATP released from endothelial cells may be involved in the CR supplementation-induced inhibition of endothelial permeability, neutrophil adhesion to endothelial cells, and the expression of adhesion molecules. It has been reported that endothelial cells release ATP during acute inflammation or shear stress (Bodin & Burnstock, 1998;2001). Like endothelial cells, epithelial cells have also been reported to release ATP (Knight et al., 2002).
Furthermore, adenosine has been shown to have an inhibitory activity against endothelial permeability and adhesion molecule expression through the adenosine A2A receptor (Haselton et al., 1993; Okusa et al., 2000; McPherson et al., 2001). We also demonstrated that the adenosine A2A receptor antagonist suppressed the CR supplementation-mediated inhibition of adhesion molecule expressions. Taken together, CR supplementation may enhance ATP release from endothelial cells by increasing PC storage, resulting in anti-inflammatory activities through the adenosine A2A receptor against endothelial cells.
In summary, CR supplementation inhibited endothelial permeability, neutrophil adhesion, and adhesion molecule expression on cultured endothelial cells. Findings in the present study suggest that CR supplementation might inhibit endothelial cell-mediated inflammation by increasing intracellular PC contents.