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Caffeic acid, a phenol found in white wine, modulates endothelial nitric oxide production and protects from oxidative stress-associated endothelial cell injury.

Migliori M, Cantaluppi V, Mannari C, Bertelli AA, Medica D, Quercia AD, Navarro V, Scatena A, Giovannini L, Biancone L, Panichi V - PLoS ONE (2015)

Bottom Line: The biological effects exerted by CAF on endothelial cells may be at least in part ascribed to modulation of NO release and by decreased ROS production.In an experimental model of kidney ischemia-reperfusion injury in mice, CAF significantly decreased tubular cell apoptosis, intraluminal cast deposition and leukocyte infiltration.The results of the present study suggest that CAF, at very low dosages similar to those observed after moderate white wine consumption, may exert a protective effect on endothelial cell function by modulating NO release independently from eNOS expression and phosphorylation.

View Article: PubMed Central - PubMed

Affiliation: Nephrology and Dialysis Unit, Versilia Hospital, Lido di Camaiore, Italy.

ABSTRACT

Introduction: Several studies demonstrated that endothelium dependent vasodilatation is impaired in cardiovascular and chronic kidney diseases because of oxidant stress-induced nitric oxide availability reduction. The Mediterranean diet, which is characterized by food containing phenols, was correlated with a reduced incidence of cardiovascular diseases and delayed progression toward end stage chronic renal failure. Previous studies demonstrated that both red and white wine exert cardioprotective effects. In particular, wine contains Caffeic acid (CAF), an active component with known antioxidant activities.

Aim of the study: The aim of the present study was to investigate the protective effect of low doses of CAF on oxidative stress-induced endothelial injury.

Results: CAF increased basal as well as acetylcholine-induced NO release by a mechanism independent from eNOS expression and phosphorylation. In addition, low doses of CAF (100 nM and 1 μM) increased proliferation and angiogenesis and inhibited leukocyte adhesion and endothelial cell apoptosis induced by hypoxia or by the uremic toxins ADMA, p-cresyl sulfate and indoxyl sulfate. The biological effects exerted by CAF on endothelial cells may be at least in part ascribed to modulation of NO release and by decreased ROS production. In an experimental model of kidney ischemia-reperfusion injury in mice, CAF significantly decreased tubular cell apoptosis, intraluminal cast deposition and leukocyte infiltration.

Conclusion: The results of the present study suggest that CAF, at very low dosages similar to those observed after moderate white wine consumption, may exert a protective effect on endothelial cell function by modulating NO release independently from eNOS expression and phosphorylation. CAF-induced NO modulation may limit cardiovascular and kidney disease progression associated with oxidative stress-mediated endothelial injury.

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CAF induced proliferation and resistance to apoptosis, decreased PBMC adhesion and triggered in vitro angiogenesis of HUVECs cultured with uremic toxins.Proliferation (XTT-based assay in A), resistance to apoptosis (TUNEL assay in B), PBMC adhesion (C) and in vitro angiogenesis on Matrigel coated-plates (representative micrographs in D, count of capillary-like structures in E) of HUVECs cultured with the uremic toxins ADMA (10 μg/ml), p-cresyl sulfate (1 μg/ml) and indoxyl sulfate (10 μg/ml) in presence or absence of CAF. Uremic toxins reduced cell viability, increased apoptosis and PBMC adhesion and abrogated angiogenesis of HUVECs (#p < 0.05 Uremic Toxins vs. Vehicle). By contrast, increasing doses of CAF (100 nM, 1μM, 10μM) increased viabilty and resistance to apoptosis (*p < 0.05 Uremic Toxins + CAF 100 nM, 1μM or 10μM vs. Uremic Toxins), and a fixed dose of CAF 1μM decreased PBMC adhesion and triggered angiogenesis of uremic toxin-treated HUVECs (*p < 0.05 Uremic Toxins + CAF 1μM vs. Uremic Toxins). Results are expressed as average±1SD of 3 different experiments.
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pone.0117530.g010: CAF induced proliferation and resistance to apoptosis, decreased PBMC adhesion and triggered in vitro angiogenesis of HUVECs cultured with uremic toxins.Proliferation (XTT-based assay in A), resistance to apoptosis (TUNEL assay in B), PBMC adhesion (C) and in vitro angiogenesis on Matrigel coated-plates (representative micrographs in D, count of capillary-like structures in E) of HUVECs cultured with the uremic toxins ADMA (10 μg/ml), p-cresyl sulfate (1 μg/ml) and indoxyl sulfate (10 μg/ml) in presence or absence of CAF. Uremic toxins reduced cell viability, increased apoptosis and PBMC adhesion and abrogated angiogenesis of HUVECs (#p < 0.05 Uremic Toxins vs. Vehicle). By contrast, increasing doses of CAF (100 nM, 1μM, 10μM) increased viabilty and resistance to apoptosis (*p < 0.05 Uremic Toxins + CAF 100 nM, 1μM or 10μM vs. Uremic Toxins), and a fixed dose of CAF 1μM decreased PBMC adhesion and triggered angiogenesis of uremic toxin-treated HUVECs (*p < 0.05 Uremic Toxins + CAF 1μM vs. Uremic Toxins). Results are expressed as average±1SD of 3 different experiments.

Mentions: Increasing doses of CAF (100 nM, 1μM, 10μM) significantly increased proliferation (Fig. 8A), and reduced apoptosis (TUNEL assay in Fig. 8B). In addition, 1μM CAF significantly reduced PBMC adhesion to HUVEC monolayers cultured under hypoxia, suggesting an anti-inflammatory effect (Fig. 8C). CAF also triggered angiogenesis of hypoxic HUVECs as shown in representative micrographs (Fig. 8D) and in count of capillary-like structure formation (Fig. 8E) on Matrigel-coated plates. To further confirm the pro-angiogenic effect of CAF on hypoxic HUVEC, we performed gene array analysis: we found that CAF up-regulated in hypoxic HUVECs the expression of several genes involved in angiogenesis, cell proliferation and resistance to apoptosis (Fig. 9). A similar protective effect of CAF on proliferation (Fig. 10A), resistance to apoptosis (Fig. 10B), PBMC adhesion (Fig. 10C) and triggering of angiogenesis (Fig. 10D-E) was also observed in HUVECs cultured in presence of the uremic toxins ADMA, p-cresyl sulfate and indoxyl sulfate known to induce endothelial injury and apoptosis through the induction of oxidative stress [37–40].


Caffeic acid, a phenol found in white wine, modulates endothelial nitric oxide production and protects from oxidative stress-associated endothelial cell injury.

Migliori M, Cantaluppi V, Mannari C, Bertelli AA, Medica D, Quercia AD, Navarro V, Scatena A, Giovannini L, Biancone L, Panichi V - PLoS ONE (2015)

CAF induced proliferation and resistance to apoptosis, decreased PBMC adhesion and triggered in vitro angiogenesis of HUVECs cultured with uremic toxins.Proliferation (XTT-based assay in A), resistance to apoptosis (TUNEL assay in B), PBMC adhesion (C) and in vitro angiogenesis on Matrigel coated-plates (representative micrographs in D, count of capillary-like structures in E) of HUVECs cultured with the uremic toxins ADMA (10 μg/ml), p-cresyl sulfate (1 μg/ml) and indoxyl sulfate (10 μg/ml) in presence or absence of CAF. Uremic toxins reduced cell viability, increased apoptosis and PBMC adhesion and abrogated angiogenesis of HUVECs (#p < 0.05 Uremic Toxins vs. Vehicle). By contrast, increasing doses of CAF (100 nM, 1μM, 10μM) increased viabilty and resistance to apoptosis (*p < 0.05 Uremic Toxins + CAF 100 nM, 1μM or 10μM vs. Uremic Toxins), and a fixed dose of CAF 1μM decreased PBMC adhesion and triggered angiogenesis of uremic toxin-treated HUVECs (*p < 0.05 Uremic Toxins + CAF 1μM vs. Uremic Toxins). Results are expressed as average±1SD of 3 different experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4390339&req=5

pone.0117530.g010: CAF induced proliferation and resistance to apoptosis, decreased PBMC adhesion and triggered in vitro angiogenesis of HUVECs cultured with uremic toxins.Proliferation (XTT-based assay in A), resistance to apoptosis (TUNEL assay in B), PBMC adhesion (C) and in vitro angiogenesis on Matrigel coated-plates (representative micrographs in D, count of capillary-like structures in E) of HUVECs cultured with the uremic toxins ADMA (10 μg/ml), p-cresyl sulfate (1 μg/ml) and indoxyl sulfate (10 μg/ml) in presence or absence of CAF. Uremic toxins reduced cell viability, increased apoptosis and PBMC adhesion and abrogated angiogenesis of HUVECs (#p < 0.05 Uremic Toxins vs. Vehicle). By contrast, increasing doses of CAF (100 nM, 1μM, 10μM) increased viabilty and resistance to apoptosis (*p < 0.05 Uremic Toxins + CAF 100 nM, 1μM or 10μM vs. Uremic Toxins), and a fixed dose of CAF 1μM decreased PBMC adhesion and triggered angiogenesis of uremic toxin-treated HUVECs (*p < 0.05 Uremic Toxins + CAF 1μM vs. Uremic Toxins). Results are expressed as average±1SD of 3 different experiments.
Mentions: Increasing doses of CAF (100 nM, 1μM, 10μM) significantly increased proliferation (Fig. 8A), and reduced apoptosis (TUNEL assay in Fig. 8B). In addition, 1μM CAF significantly reduced PBMC adhesion to HUVEC monolayers cultured under hypoxia, suggesting an anti-inflammatory effect (Fig. 8C). CAF also triggered angiogenesis of hypoxic HUVECs as shown in representative micrographs (Fig. 8D) and in count of capillary-like structure formation (Fig. 8E) on Matrigel-coated plates. To further confirm the pro-angiogenic effect of CAF on hypoxic HUVEC, we performed gene array analysis: we found that CAF up-regulated in hypoxic HUVECs the expression of several genes involved in angiogenesis, cell proliferation and resistance to apoptosis (Fig. 9). A similar protective effect of CAF on proliferation (Fig. 10A), resistance to apoptosis (Fig. 10B), PBMC adhesion (Fig. 10C) and triggering of angiogenesis (Fig. 10D-E) was also observed in HUVECs cultured in presence of the uremic toxins ADMA, p-cresyl sulfate and indoxyl sulfate known to induce endothelial injury and apoptosis through the induction of oxidative stress [37–40].

Bottom Line: The biological effects exerted by CAF on endothelial cells may be at least in part ascribed to modulation of NO release and by decreased ROS production.In an experimental model of kidney ischemia-reperfusion injury in mice, CAF significantly decreased tubular cell apoptosis, intraluminal cast deposition and leukocyte infiltration.The results of the present study suggest that CAF, at very low dosages similar to those observed after moderate white wine consumption, may exert a protective effect on endothelial cell function by modulating NO release independently from eNOS expression and phosphorylation.

View Article: PubMed Central - PubMed

Affiliation: Nephrology and Dialysis Unit, Versilia Hospital, Lido di Camaiore, Italy.

ABSTRACT

Introduction: Several studies demonstrated that endothelium dependent vasodilatation is impaired in cardiovascular and chronic kidney diseases because of oxidant stress-induced nitric oxide availability reduction. The Mediterranean diet, which is characterized by food containing phenols, was correlated with a reduced incidence of cardiovascular diseases and delayed progression toward end stage chronic renal failure. Previous studies demonstrated that both red and white wine exert cardioprotective effects. In particular, wine contains Caffeic acid (CAF), an active component with known antioxidant activities.

Aim of the study: The aim of the present study was to investigate the protective effect of low doses of CAF on oxidative stress-induced endothelial injury.

Results: CAF increased basal as well as acetylcholine-induced NO release by a mechanism independent from eNOS expression and phosphorylation. In addition, low doses of CAF (100 nM and 1 μM) increased proliferation and angiogenesis and inhibited leukocyte adhesion and endothelial cell apoptosis induced by hypoxia or by the uremic toxins ADMA, p-cresyl sulfate and indoxyl sulfate. The biological effects exerted by CAF on endothelial cells may be at least in part ascribed to modulation of NO release and by decreased ROS production. In an experimental model of kidney ischemia-reperfusion injury in mice, CAF significantly decreased tubular cell apoptosis, intraluminal cast deposition and leukocyte infiltration.

Conclusion: The results of the present study suggest that CAF, at very low dosages similar to those observed after moderate white wine consumption, may exert a protective effect on endothelial cell function by modulating NO release independently from eNOS expression and phosphorylation. CAF-induced NO modulation may limit cardiovascular and kidney disease progression associated with oxidative stress-mediated endothelial injury.

Show MeSH
Related in: MedlinePlus