Minocycline reduces plaque size in diet induced atherosclerosis via p27Kip1

ObjectiveMinocycline, 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.MethodsUsing 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 p27Kip1 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).Results and conclusionMinocycline 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 p27Kip1 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 p27Kip1 expression in VSMC as efficiently as the specific PARP-1 inhibitor PJ 34. Knock down of p27Kip1 abolished the antiproliferative effect of minocycline. These data establish a novel antiatherosclerotic mechanism of minocycline during de novo atherogenesis, which depends on p27Kip1 mediated inhibition of VSMC proliferation.