PMID- 20557886
OWN - NLM
STAT- MEDLINE
DCOM- 20101228
LR  - 20100903
IS  - 1879-1484 (Electronic)
IS  - 0021-9150 (Linking)
VI  - 212
IP  - 1
DP  - 2010 Sep
TI  - The androgen derivative 5alpha-androstane-3beta,17beta-diol inhibits tumor 
      necrosis factor alpha and lipopolysaccharide induced inflammatory response in 
      human endothelial cells and in mice aorta.
PG  - 100-6
LID - 10.1016/j.atherosclerosis.2010.05.015 [doi]
AB  - BACKGROUND: An increasing body of evidence suggests that testosterone may exert 
      beneficial effects against the development of atherosclerosis. These effects are 
      thought to be the consequence of its conversion into estradiol and the activation 
      of the estrogen receptors; however a direct role of androgens, such as 
      dihydrotestosterone, has also been proposed. More recently, it has been shown 
      that the transformation of the dihydrotestosterone to 
      5alpha-androstane-3alpha,17beta-diol (3alpha-diol) and 
      5alpha-androstane-3beta,17beta-diol (3beta-Adiol), generates two molecules unable 
      to bind the androgen receptor, but with a high affinity for the estrogen 
      receptors (ERs) in particular the beta isoform. As the actions of testosterone 
      may result from the balance between androgenic and estrogenic molecules 
      originating from its catabolism, we investigated the effects of the 3beta-Adiol 
      on inflammatory responses in vitro in human endothelial cells and ex vivo in mice 
      aortas. METHODS AND RESULTS: 3beta-Adiol reverts the pro-inflammatory gene 
      expression pattern induced by TNF-alpha in HUVECs as determined by a cDNA 
      microrray approach. Q-real-time PCR and protein array approaches confirmed that 
      TNF-alpha-induced ICAM-1, VCAM-1 and ELAM-1 as well as MCP-1 and IL-6 induction 
      was affected upon 3beta-Adiol pre-incubation. ICI 182780, an estrogen receptor 
      antagonist and R,R-THC, an estrogen receptor beta antagonist, counteracted the 
      effect of 3beta-Adiol while bicalutamide, an androgen receptor antagonist, had 
      minor effects. 3beta-Adiol exerted a similar action on macrophages. Finally in 
      castrated male mice, 3beta-Adiol significantly counteracted the LPS mediated mRNA 
      induction of IL-6, ELAM-1and PECAM-1 in the aortas. CONCLUSION: 3beta-Adiol 
      reverts in vitro the TNF-alpha and LPS induced pro-inflammatory activation of 
      endothelial cells and macrophages. 3beta-Adiol in vivo modulates the inflammatory 
      response induced by LPS in the arterial vascular wall.
CI  - Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
FAU - Norata, Giuseppe Danilo
AU  - Norata GD
AD  - Department of Pharmacological Sciences, Universita degli Studi di Milano, Italy. 
      Danilo.Norata@unimi.it
FAU - Cattaneo, Paola
AU  - Cattaneo P
FAU - Poletti, Angelo
AU  - Poletti A
FAU - Catapano, Alberico Luigi
AU  - Catapano AL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100519
PL  - Ireland
TA  - Atherosclerosis
JT  - Atherosclerosis
JID - 0242543
RN  - 0 (Androgen Antagonists)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Estrogen Antagonists)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 25126-76-5 (Androstane-3,17-diol)
SB  - IM
MH  - Androgen Antagonists/pharmacology
MH  - Androstane-3,17-diol/*administration & dosage
MH  - Animals
MH  - Anti-Inflammatory Agents/*administration & dosage
MH  - Aorta/*drug effects/immunology
MH  - Endothelial Cells/*drug effects/immunology
MH  - Estrogen Antagonists/pharmacology
MH  - Gene Expression Profiling/methods
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Inflammation/genetics/immunology/*prevention & control
MH  - Inflammation Mediators/*metabolism
MH  - Lipopolysaccharides/*pharmacology
MH  - Macrophages/drug effects/immunology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Oligonucleotide Array Sequence Analysis
MH  - Orchiectomy
MH  - Protein Array Analysis
MH  - RNA, Messenger/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Necrosis Factor-alpha/*metabolism
MH  - U937 Cells
EDAT- 2010/06/19 06:00
MHDA- 2010/12/29 06:00
CRDT- 2010/06/19 06:00
PHST- 2009/12/22 00:00 [received]
PHST- 2010/05/10 00:00 [revised]
PHST- 2010/05/10 00:00 [accepted]
PHST- 2010/06/19 06:00 [entrez]
PHST- 2010/06/19 06:00 [pubmed]
PHST- 2010/12/29 06:00 [medline]
AID - S0021-9150(10)00393-X [pii]
AID - 10.1016/j.atherosclerosis.2010.05.015 [doi]
PST - ppublish
SO  - Atherosclerosis. 2010 Sep;212(1):100-6. doi: 
      10.1016/j.atherosclerosis.2010.05.015. Epub 2010 May 19.