Adrenomedullin and Nitric Oxide Inhibit Human Endothelial Cell Apoptosis via a Cyclic GMP-Independent Mechanism

Sata, Masataka; Kakoki, Masao; Nagata, Daisuke; Nishimatsu, Hiroaki; Suzuki, Emiko; Aoyagi, Takaaki; Sugiura, Seiryo; Kojima, Hirotatsu; Nagano, Tetsuo; Kangawa, Kenji; Matsuo, Hisayuki; Omata, Masao; Nagai, Ryozo; Hirata, Yasunobu

doi:10.1161/01.hyp.36.1.83

Cited by 127 publications

(79 citation statements)

References 57 publications

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“…Such a result has been demonstrated in breast cancer [16], endometrial cancer [17], and endothelial [18] cells. Culture of cells under stressful conditions, such as exposure to TNFa [19], hypoxia [17] or serum deprivation [20,18] stimulates AM expression. Since our previous publications showed that AM causes cell cycle arrest and subsequent cell growth inhibition in PC-3 and LNCaP cells, we hypothesized in the present study that AM would favor cells to undergo induced-apoptosis.…”

Section: Introductionmentioning

confidence: 62%

“…Resistance to apoptosis is related in these cells to a decrease in the pro-apoptotic molecules Bax and BID, and several caspases [29]. AM exerts an anti-apoptotic effect on endothelial cells cultured in serum-free conditions [18]. Such an effect occurs via cGMP-and Bcl-independent mechanisms [18].…”

Section: Discussionmentioning

confidence: 99%

“…AM exerts an anti-apoptotic effect on endothelial cells cultured in serum-free conditions [18]. Such an effect occurs via cGMP-and Bcl-independent mechanisms [18]. Culture of endometrial cancer cells under hypoxic conditions leads to programmed cell death, which is prevented if cells are treated with or overexpress AM [17].…”

Section: Discussionmentioning

confidence: 99%

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Adrenomedullin prevents apoptosis in prostate cancer cells

Abasolo

Montuenga

Calvo

2006

Regulatory Peptides

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The 52-aminoacid peptide adrenomedullin (AM) is expressed in the normal and malignant prostate. We have previously shown that prostate cancer cells produce and secrete AM, which acts as an autocrine growth inhibitory factor. We have evaluated in the present study the role of AM in prostate cancer cell apoptosis, induced either by serum deprivation or treatment with the chemotherapeutic agent etoposide (which acts as an inhibitor of topoisomerase II). For this purpose we over-expressed AM in PC-3, DU 145 and LNCaP cells, which were transfected with an expression vector carrying AM. We also treated the parental cell lines with synthetic AM in normal culture conditions and in conditions of induced-apoptosis. After serum removal, AM prevented apoptosis in DU 145 and PC-3 cells, but not in LNCaP cells. When treated with etoposide, AM prevented apoptosis in PC-3 and LNCaP cells, but not in DU 145 cells. Cell cycle analysis demonstrated a significant decrease in the percentage of AM-overexpressing PC-3 cells in the subG0/G1 phase after treatment with etoposide, as compared to the percentage of mocktransfected PC-3 treated cells. Western blot showed that protein levels of phosphorylated ERK1/2 increased in parental PC-3 cells after treatment with etoposide. In PC-3 cells overexpressing AM, phosphorylated ERK1/2 basal levels were lower than basal levels of parental PC-3 cells, and treatment with etoposide did not result in such an increase. Etoposide produced a significant increase in cleaved PARP in parental PC-3 cells. However, PC-3 clones overexpressing AM that were treated with etoposide only showed a mild increase in fragmented PARP. The ratio Bcl-2/Bax was reduced in parental or mock-transfected PC-3 cells after treatment with etoposide. On the contrary, this ratio was not reduced in PC-3 clones with AM overexpression that were treated with etoposide. All these data demonstrate that AM plays a protective role against induced apoptosis in prostate cancer cells. These results may have important implications in prostate cancer resistance to chemotherapeutic agents. D

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Section: Introductionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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Adrenomedullin prevents apoptosis in prostate cancer cells

Abasolo

Montuenga

Calvo

2006

Regulatory Peptides

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“…It has also been reported that under ischemic conditions endothelial cells undergo apoptosis, but the administration of statins may prevent the decrease of existing capillary vessels resulting from ischemia. 19 Sata et al 20 reported that they administered Ach into the aorta of mice and measured the NO production as an index of relaxation response of the medial smooth muscle. After a 3-day administration of statins, the dilator response of blood vessels was significantly larger than that in the control group.…”

Section: Discussionmentioning

confidence: 99%

The effects of atorvastatin on coronary endothelial function in patients with recent myocardial infarction

et al. 2006

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SummaryBackground: Endothelial dysfunction is a key early event in atherosclerosis that occurs in acute coronary syndrome. It was reported that atorvastatin improves the endothelial function of skeletal muscle vessels, but the effect on the coronary artery is unknown.Hypothesis: The purpose of this study is to determine the effects of atorvastatin on coronary endothelial function in humans.Methods: Non-infarct-related coronary arteries of 48 patients with acute myocardial infarction who had undergone successful percutaneous transluminal coronary angioplasty were examined. Three groups were studied: hyperlipidemia with use of atorvastatin (Group 1, n = 17), hyperlipidemia without statin use (Group 2, n = 18), and normal cholesterol level controls (Group 3, n = 13). Statin treatment was started at discharge. Acetylcholine (Ach) was infused into the coronary artery and the diameter was assessed by quantitative angiography at baseline and after 6 months.Results: Acetylcholine given in doses of 1, 3, 10, and 30 mg/min increased the coronary artery diameter change in a dose-dependent manner. In the initial study, patients in the three groups had similar responses to Ach. The mean diameter change after 6 months was significantly improved in Group 1 compared with Groups 2 and 3 (Ϫ11 ± 3% vs. Ϫ20

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“…As we have previously shown that nitric oxide has an anti-apoptotic effect in endothelial cells, 22 we used the WST-1 assay to investigate whether the nitric oxide synthase inhibitor L-NAME could inhibit the anti-apoptotic cell survival effect of NcaAMPK. Although we used L-NAME concentrations from 1.0 to 5.0 mmol l À1 , L-NAME pretreatment did not inhibit cell survival (Figure 4c).…”

Section: Ampk Inhibits Anoxia-induced Apoptosis Of Huvecs D Nagata Et Almentioning

confidence: 99%

A new constitutively active mutant of AMP-activated protein kinase inhibits anoxia-induced apoptosis of vascular endothelial cell

et al. 2009

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The inhibition of apoptotic changes in vascular endothelial cells is important for preventing vascular damage from hypoxia. AMP-activated protein kinase (AMPK) has recently been identified as playing a role in vascular protection. Although the chemical reagent 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR) has been used to stimulate AMPK activity, AICAR has been associated with several nonspecific reactions. We therefore constructed a new constitutively active mutant of AMPKa1 (NcaAMPK), which lacks the autoinhibitory domain in AMPKa1 and in which threonine 172 has been replaced with aspartate. We investigated whether NcaAMPK has an anti-apoptotic effect in vascular endothelial cells under anoxic conditions. NcaAMPK, or green fluorescent protein (GFP) as a control, was overexpressed in human umbilical vein endothelial cells (HUVECs). After HUVECs were incubated for 40 h under normoxic or anoxic conditions, we examined cell viability, caspase 3/7 activity, and expression and phosphorylation levels of apoptosis-related proteins. Cell viabilities under anoxic conditions were improved in NcaAMPK-overexpressing cells. Anoxia increased caspase 3/7 activity, but NcaAMPK reduced this increase significantly. NcaAMPK overexpression increased protein kinase B/Akt Ser473 and endothelial nitric oxide synthase Ser1177 phosphorylation, but pretreatment with the nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) did not decrease the viability of NcaAMPK-overexpressing HUVECs. Furthermore, co-expression of a dominant-negative Akt reduced the improvement in cell viability and the suppression of poly (ADP-ribose) polymerase cleavage by NcaAMPK under anoxic conditions. In conclusion, NcaAMPK inhibited anoxia-induced apoptosis in vascular endothelial cells through Akt activation, suggesting that activation of AMPK might protect against ischemic vascular injury.

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Adrenomedullin and Nitric Oxide Inhibit Human Endothelial Cell Apoptosis via a Cyclic GMP-Independent Mechanism

Cited by 127 publications

References 57 publications

Adrenomedullin prevents apoptosis in prostate cancer cells

Adrenomedullin prevents apoptosis in prostate cancer cells

The effects of atorvastatin on coronary endothelial function in patients with recent myocardial infarction

A new constitutively active mutant of AMP-activated protein kinase inhibits anoxia-induced apoptosis of vascular endothelial cell

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