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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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Related in: MedlinePlus

Modulation of gene array profiling of hypoxic HUVECs induced by CAF 1μM (angiogenesis-related genes).The graph shows the fold variation of angiogenesis-related genes between HUVECs stimulated with Hypoxia + CAF 1μM vs. Hypoxia in a single experiment. Samples were normalized for the signals found in housekeeping genes [actin, glyceraldehyde 3 phosphate dehydrogenase (GAPDH)]. Three independent experiments were performed with similar results. Gene table: AKT1, V-akt murine thymoma viral oncogene homolog 1; ANGPT1, Angiopoietin 1; ANGPTL3, Angiopoietin-like 3; ANGPTL4, Angiopoietin-like 4; BAI1, Brain-specific angiogenesis inhibitor 1; CDH5, Cadherin 5, type 2 (vascular endothelium); COL18A1, Collagen, type XVIII, α1; COL4A3, Collagen, type IV, α3 (Goodpasture antigen); CXCL10, Chemokine (C-X-C motif) ligand 10; CXCL9, Chemokine (C-X-C motif) ligand 9; S1PR1, Sphingosine-1-phosphate receptor 1; EGF, Epidermal growth factor; EREG, Epiregulin; FGFR3, fibroblast growth factor receptor 3; FIGF, C-fos induced growth factor (vascular endothelial growth factor D); FLT1, Fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor); HAND2, Heart and neural crest derivatives expressed 2; HGF, Hepatocyte growth factor (hepapoietin A; scatter factor); HPSE, Heparanase; ID1, Inhibitor of DNA binding 1, dominant negative helix-loop-helix protein; IFNA1, Interferon, α1; IFNB1, Interferon, β1, fibroblast; IFNG, Interferon, γ; IGF1, Insulin-like growth factor 1 (somatomedin C); IL1B, Interleukin 1, β; IL6, Interleukin 6 (interferon, β2); IL8, Interleukin 8; KDR, Kinase insert domain receptor (a type III receptor tyrosine kinase); LAMA5, Laminin, α5; LECT1, Leukocyte cell derived chemotaxin 1; LEP, Leptin; MMP2, Matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); NOTCH4, Notch 4; PF4, Platelet factor 4; PGF, Placental growth factor; PLAU, Plasminogen activator, urokinase; PLG, Plasminogen; PROK2, Prokineticin 2; PTGS1, Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase); SPHK1, Sphingosine kinase 1; STAB1, Stabilin 1; TEK, TEK tyrosine kinase, endothelial/Tie-2; TGFBR1 transforming growth factor, β receptor 1; TIMP1, TIMP metallopeptidase inhibitor 1; TIMP3, TIMP metallopeptidase inhibitor 3; TNF, Tumor necrosis factor; TNFAIP2, Tumor necrosis factor, α-induced protein 2; VEGFA, Vascular endothelial growth factor A; VEGFC, Vascular endothelial growth factor C.
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pone.0117530.g009: Modulation of gene array profiling of hypoxic HUVECs induced by CAF 1μM (angiogenesis-related genes).The graph shows the fold variation of angiogenesis-related genes between HUVECs stimulated with Hypoxia + CAF 1μM vs. Hypoxia in a single experiment. Samples were normalized for the signals found in housekeeping genes [actin, glyceraldehyde 3 phosphate dehydrogenase (GAPDH)]. Three independent experiments were performed with similar results. Gene table: AKT1, V-akt murine thymoma viral oncogene homolog 1; ANGPT1, Angiopoietin 1; ANGPTL3, Angiopoietin-like 3; ANGPTL4, Angiopoietin-like 4; BAI1, Brain-specific angiogenesis inhibitor 1; CDH5, Cadherin 5, type 2 (vascular endothelium); COL18A1, Collagen, type XVIII, α1; COL4A3, Collagen, type IV, α3 (Goodpasture antigen); CXCL10, Chemokine (C-X-C motif) ligand 10; CXCL9, Chemokine (C-X-C motif) ligand 9; S1PR1, Sphingosine-1-phosphate receptor 1; EGF, Epidermal growth factor; EREG, Epiregulin; FGFR3, fibroblast growth factor receptor 3; FIGF, C-fos induced growth factor (vascular endothelial growth factor D); FLT1, Fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor); HAND2, Heart and neural crest derivatives expressed 2; HGF, Hepatocyte growth factor (hepapoietin A; scatter factor); HPSE, Heparanase; ID1, Inhibitor of DNA binding 1, dominant negative helix-loop-helix protein; IFNA1, Interferon, α1; IFNB1, Interferon, β1, fibroblast; IFNG, Interferon, γ; IGF1, Insulin-like growth factor 1 (somatomedin C); IL1B, Interleukin 1, β; IL6, Interleukin 6 (interferon, β2); IL8, Interleukin 8; KDR, Kinase insert domain receptor (a type III receptor tyrosine kinase); LAMA5, Laminin, α5; LECT1, Leukocyte cell derived chemotaxin 1; LEP, Leptin; MMP2, Matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); NOTCH4, Notch 4; PF4, Platelet factor 4; PGF, Placental growth factor; PLAU, Plasminogen activator, urokinase; PLG, Plasminogen; PROK2, Prokineticin 2; PTGS1, Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase); SPHK1, Sphingosine kinase 1; STAB1, Stabilin 1; TEK, TEK tyrosine kinase, endothelial/Tie-2; TGFBR1 transforming growth factor, β receptor 1; TIMP1, TIMP metallopeptidase inhibitor 1; TIMP3, TIMP metallopeptidase inhibitor 3; TNF, Tumor necrosis factor; TNFAIP2, Tumor necrosis factor, α-induced protein 2; VEGFA, Vascular endothelial growth factor A; VEGFC, Vascular endothelial growth factor C.

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)

Modulation of gene array profiling of hypoxic HUVECs induced by CAF 1μM (angiogenesis-related genes).The graph shows the fold variation of angiogenesis-related genes between HUVECs stimulated with Hypoxia + CAF 1μM vs. Hypoxia in a single experiment. Samples were normalized for the signals found in housekeeping genes [actin, glyceraldehyde 3 phosphate dehydrogenase (GAPDH)]. Three independent experiments were performed with similar results. Gene table: AKT1, V-akt murine thymoma viral oncogene homolog 1; ANGPT1, Angiopoietin 1; ANGPTL3, Angiopoietin-like 3; ANGPTL4, Angiopoietin-like 4; BAI1, Brain-specific angiogenesis inhibitor 1; CDH5, Cadherin 5, type 2 (vascular endothelium); COL18A1, Collagen, type XVIII, α1; COL4A3, Collagen, type IV, α3 (Goodpasture antigen); CXCL10, Chemokine (C-X-C motif) ligand 10; CXCL9, Chemokine (C-X-C motif) ligand 9; S1PR1, Sphingosine-1-phosphate receptor 1; EGF, Epidermal growth factor; EREG, Epiregulin; FGFR3, fibroblast growth factor receptor 3; FIGF, C-fos induced growth factor (vascular endothelial growth factor D); FLT1, Fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor); HAND2, Heart and neural crest derivatives expressed 2; HGF, Hepatocyte growth factor (hepapoietin A; scatter factor); HPSE, Heparanase; ID1, Inhibitor of DNA binding 1, dominant negative helix-loop-helix protein; IFNA1, Interferon, α1; IFNB1, Interferon, β1, fibroblast; IFNG, Interferon, γ; IGF1, Insulin-like growth factor 1 (somatomedin C); IL1B, Interleukin 1, β; IL6, Interleukin 6 (interferon, β2); IL8, Interleukin 8; KDR, Kinase insert domain receptor (a type III receptor tyrosine kinase); LAMA5, Laminin, α5; LECT1, Leukocyte cell derived chemotaxin 1; LEP, Leptin; MMP2, Matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); NOTCH4, Notch 4; PF4, Platelet factor 4; PGF, Placental growth factor; PLAU, Plasminogen activator, urokinase; PLG, Plasminogen; PROK2, Prokineticin 2; PTGS1, Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase); SPHK1, Sphingosine kinase 1; STAB1, Stabilin 1; TEK, TEK tyrosine kinase, endothelial/Tie-2; TGFBR1 transforming growth factor, β receptor 1; TIMP1, TIMP metallopeptidase inhibitor 1; TIMP3, TIMP metallopeptidase inhibitor 3; TNF, Tumor necrosis factor; TNFAIP2, Tumor necrosis factor, α-induced protein 2; VEGFA, Vascular endothelial growth factor A; VEGFC, Vascular endothelial growth factor C.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390339&req=5

pone.0117530.g009: Modulation of gene array profiling of hypoxic HUVECs induced by CAF 1μM (angiogenesis-related genes).The graph shows the fold variation of angiogenesis-related genes between HUVECs stimulated with Hypoxia + CAF 1μM vs. Hypoxia in a single experiment. Samples were normalized for the signals found in housekeeping genes [actin, glyceraldehyde 3 phosphate dehydrogenase (GAPDH)]. Three independent experiments were performed with similar results. Gene table: AKT1, V-akt murine thymoma viral oncogene homolog 1; ANGPT1, Angiopoietin 1; ANGPTL3, Angiopoietin-like 3; ANGPTL4, Angiopoietin-like 4; BAI1, Brain-specific angiogenesis inhibitor 1; CDH5, Cadherin 5, type 2 (vascular endothelium); COL18A1, Collagen, type XVIII, α1; COL4A3, Collagen, type IV, α3 (Goodpasture antigen); CXCL10, Chemokine (C-X-C motif) ligand 10; CXCL9, Chemokine (C-X-C motif) ligand 9; S1PR1, Sphingosine-1-phosphate receptor 1; EGF, Epidermal growth factor; EREG, Epiregulin; FGFR3, fibroblast growth factor receptor 3; FIGF, C-fos induced growth factor (vascular endothelial growth factor D); FLT1, Fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor); HAND2, Heart and neural crest derivatives expressed 2; HGF, Hepatocyte growth factor (hepapoietin A; scatter factor); HPSE, Heparanase; ID1, Inhibitor of DNA binding 1, dominant negative helix-loop-helix protein; IFNA1, Interferon, α1; IFNB1, Interferon, β1, fibroblast; IFNG, Interferon, γ; IGF1, Insulin-like growth factor 1 (somatomedin C); IL1B, Interleukin 1, β; IL6, Interleukin 6 (interferon, β2); IL8, Interleukin 8; KDR, Kinase insert domain receptor (a type III receptor tyrosine kinase); LAMA5, Laminin, α5; LECT1, Leukocyte cell derived chemotaxin 1; LEP, Leptin; MMP2, Matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); NOTCH4, Notch 4; PF4, Platelet factor 4; PGF, Placental growth factor; PLAU, Plasminogen activator, urokinase; PLG, Plasminogen; PROK2, Prokineticin 2; PTGS1, Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase); SPHK1, Sphingosine kinase 1; STAB1, Stabilin 1; TEK, TEK tyrosine kinase, endothelial/Tie-2; TGFBR1 transforming growth factor, β receptor 1; TIMP1, TIMP metallopeptidase inhibitor 1; TIMP3, TIMP metallopeptidase inhibitor 3; TNF, Tumor necrosis factor; TNFAIP2, Tumor necrosis factor, α-induced protein 2; VEGFA, Vascular endothelial growth factor A; VEGFC, Vascular endothelial growth factor C.
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