PMID- 23868084
OWN - NLM
STAT- MEDLINE
DCOM- 20140529
LR  - 20161125
IS  - 1473-5598 (Electronic)
IS  - 0263-6352 (Linking)
VI  - 31
IP  - 10
DP  - 2013 Oct
TI  - Angiotensin-converting-enzyme inhibition counteracts angiotensin II-mediated 
      endothelial cell dysfunction by modulating the p38/SirT1 axis.
PG  - 1972-83
LID - 10.1097/HJH.0b013e3283638b32 [doi]
AB  - OBJECTIVE: Oxidative stress has been linked to endothelial dysfunction and 
      angiotensin II stimulates the reactive oxygen species production contributing to 
      several cardiovascular diseases. We have studied the chain of events induced by 
      angiotensin-converting-enzyme (ACE) activation in vascular umbilical vein 
      endothelial cells (HUVECs) by using an ACE inhibitor such as zofenoprilat. 
      METHODS: We used specific assay to measure the superoxide anion production, 
      tetrazolium bromide (MTT) assay for cell viability, terminal deoxynucleotidyl 
      transferase-mediated dUTP nick end labeling (TUNEL) assay for cell apoptosis, and 
      western blot for protein analysis in the study. RESULTS: Zofenoprilat counteracts 
      the superoxide anion production and cell apoptosis induced by angiotensin I 
      treatment by blocking the extrinsic caspase cascade, NF-kB and p38 activation. 
      p38 inhibitor SB203580 reverted the angiotensin II oxidant effects while the p38 
      constitutively activation, by MKK6 transfection, abrogated the zofenoprilat 
      effects. Characterizing the zofenoprilat downstream effector we found that 
      zofenoprilat reverted the SirT-1 downregulation induced by angiotensin II. p38 
      activation by angiotensin II was strictly correlated with SirT1 protein 
      downregulation; SB203580 significantly prevented SirT1 downregulation induced by 
      angiotensin II while the p38 constitutive activation abolished SIRT1 protein 
      basal levels. p38 directly bound SirT1 sequestering it in the cytoplasm. SirT1 
      inhibition by sirtinol annulled zofenoprilat action while SirT1 overexpression 
      reverted the cytotoxic effects of angiotensin II. Finally, zofenoprilat 
      negatively controlled angiotensin I receptor protein expression through SirT1. 
      CONCLUSION: The p38-SirT1 axis is found markedly relevant in modulating the 
      cardiovascular benefit deriving from ACE-inhibitors and might represent a novel 
      target for innovative drugs in cardiovascular prevention.
FAU - Marampon, Francesco
AU  - Marampon F
AD  - aDepartment of Applied Clinical Sciences and Biotechnology, University of 
      L'Aquila bDepartment MeSVA, University of L'Aquila, L'Aquila, Italy cDepartment 
      of Molecular Immunology, Virology, and Medical Genetics, The Ohio State 
      University, Columbus, Ohio, USA dPreclinical Development Department, Menarini 
      Ricerche, Firenze, Italy *Francesco Marampon and Giovanni L. Gravina contributed 
      equally to the writing of this article.
FAU - Gravina, Giovanni L
AU  - Gravina GL
FAU - Scarsella, Luca
AU  - Scarsella L
FAU - Festuccia, Claudio
AU  - Festuccia C
FAU - Lovat, Francesca
AU  - Lovat F
FAU - Ciccarelli, Carmela
AU  - Ciccarelli C
FAU - Zani, Bianca M
AU  - Zani BM
FAU - Polidoro, Lorella
AU  - Polidoro L
FAU - Grassi, Davide
AU  - Grassi D
FAU - Desideri, Giovambattista
AU  - Desideri G
FAU - Evangelista, Stefano
AU  - Evangelista S
FAU - Ferri, Claudio
AU  - Ferri C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - J Hypertens
JT  - Journal of hypertension
JID - 8306882
RN  - 0 (Angiotensin-Converting Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Pyridines)
RN  - 0 (Reactive Oxygen Species)
RN  - 11062-77-4 (Superoxides)
RN  - 11128-99-7 (Angiotensin II)
RN  - 4G4WDK2YBS (zofenoprilate)
RN  - 9G64RSX1XD (Captopril)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 6)
RN  - EC 2.7.12.2 (MAP2K6 protein, human)
RN  - EC 3.5.1.- (SIRT1 protein, human)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - OU13V1EYWQ (SB 203580)
SB  - IM
MH  - Angiotensin II/*metabolism
MH  - Angiotensin-Converting Enzyme Inhibitors/*pharmacology
MH  - Apoptosis
MH  - Captopril/analogs & derivatives/pharmacology
MH  - Cell Nucleus/metabolism
MH  - Cell Survival
MH  - Endothelial Cells/*cytology/metabolism
MH  - Gene Expression Regulation
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - MAP Kinase Kinase 6/metabolism
MH  - Oxidative Stress
MH  - Pyridines/pharmacology
MH  - Reactive Oxygen Species
MH  - Sirtuin 1/*metabolism
MH  - Superoxides/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/*metabolism
EDAT- 2013/07/23 06:00
MHDA- 2014/05/30 06:00
CRDT- 2013/07/23 06:00
PHST- 2013/07/23 06:00 [entrez]
PHST- 2013/07/23 06:00 [pubmed]
PHST- 2014/05/30 06:00 [medline]
AID - 10.1097/HJH.0b013e3283638b32 [doi]
PST - ppublish
SO  - J Hypertens. 2013 Oct;31(10):1972-83. doi: 10.1097/HJH.0b013e3283638b32.