Poly(ADP-ribose) polymerase 1 inhibition protects against low shear stress induced inflammation

Abstract

Background: Atherosclerosis begins as local inflammation of vessels at sites of disturbed flow, where low shear stress (LSS) leads to mechanical irritation and plaque development and progression. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with the inflammation response during atherosclerosis. We investigated the role and underlying mechanism of PARP-1 in LSS-induced inflammation in human umbilical vein endothelial cells (HUVECs).

Methods and results: HUVECs were simulated by LSS (0.4Pa). PARP-1 expression was inhibited by ABT888 or siRNA. The inducible nitric oxide synthase (iNOS) and intercellular adhesion molecular-1 (ICAM-1) expression was regulated by LSS in a time dependent manner. LSS could increase superoxide production and 3-nitrotyrosine formation. LSS induced DNA damage as assessed by H2A.X phosphorylation and comet assay. Compared with cells under static, LSS increased PARP-1 expression and PAR formation via MEK/ERK signaling pathway. PARP-1 inhibition increased Sirt1 activity through an increased intracellular nicotinamide adenine dinucleotide (NAD(+)) level. Moreover, PARP-1 inhibition attenuated LSS-induced iNOS and ICAM-1 upregulation by inhibiting nuclear factor kappa B (NF-κB) nuclear translocation and activity, with a reduced NF-κB phosphorylation.

Conclusions: LSS induced oxidative damage and PARP-1 activation via MEK/ERK pathway. PARP-1 inhibition restored Sirt1 activity by increasing NAD(+) level and decreased iNOS and ICAM-1 expression by inhibiting NF-κB nuclear translocation and activity as well as NF-κB phosphorylation. PARP-1 played a fundamental role in LSS induced inflammation. Inhibition of PARP-1 might be a mechanism for treatment of inflammation response during atherosclerosis.