title: Minocycline reduces plaque size in diet induced atherosclerosis via p27(Kip1).
abstract: OBJECTIVE
  Minocycline, a tetracycline derivate, mediates vasculoprotective effects independent of its antimicrobial properties. Thus, minocycline protects against diabetic nephropathy and reduces neointima formation following vascular injury through inhibition of apoptosis or migration, respectively. Whether minocycline has an effect on primary atherogenesis remains unknown.
  
  
  METHODS
  Using morphological and immunohistochemical analyses we determined de novo atherogenesis in ApoE-/- mice receiving a high fat diet (HFD) with or without minocycline treatment. The effect of minocycline on proliferation, expression of p27(Kip1) or PARP-1 (Poly [ADP-ribose] polymerase 1), or on PAR (poly ADP-ribosylation) modification in vascular smooth muscle cells (VSMC) was analyzed in ex vivo and in vitro (primary human and mouse VSMC).
  
  
  CONCLUSIONS
  Minocycline reduced plaque size and stenosis in ApoE-/- HFD mice. This was associated with a lower number and less proliferation of VSMC, reduced PAR (poly ADP-ribosylation) modification and increased p27(Kip1) expression within the plaques. In agreement with the ex vivo data minocycline reduced proliferation, PARP-1 expression, PAR modification while inducing p27 expression in human and mouse VSMC in vitro. These effects were observed at a low minocycline concentration (10 μM), which had no effect on VSMC migration or apoptosis. Minocycline inhibited PARP-1 and induced p27(Kip1) expression in VSMC as efficiently as the specific PARP-1 inhibitor PJ 34. Knock down of p27(Kip1) abolished the antiproliferative effect of minocycline. These data establish a novel antiatherosclerotic mechanism of minocycline during de novo atherogenesis, which depends on p27(Kip1) mediated inhibition of VSMC proliferation.
authors: Internal Medicine I and Clinical Chemistry, University of Heidelberg, INF 410, 69120 Heidelberg, Germany.
authors: Khurrum
authors: K
authors: Shahzad
authors: Madhusudhan
authors: M
authors: Thati
authors: Hongjie
authors: H
authors: Wang
authors: Muhammed
authors: M
authors: Kashif
authors: Juliane
authors: J
authors: Wolter
authors: Satish
authors: S
authors: Ranjan
authors: Tao
authors: T
authors: He
authors: Qianxing
authors: Q
authors: Zhou
authors: Erwin
authors: E
authors: Blessing
authors: Angelika
authors: A
authors: Bierhaus
authors: Peter P
authors: PP
authors: Nawroth
authors: Berend
authors: B
authors: Isermann
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000378:metabolism*; D059305:Diet, High-Fat; D006801:Humans; D051379:Mice; D008911:Minocycline / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D010616:Phenanthrenes / Q000494:pharmacology; D058226:Plaque, Atherosclerotic / Q000517:prevention & control*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D050760:Cyclin-Dependent Kinase Inhibitor p27; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D008911:Minocycline