NAD + overconsumption by poly (ADP-ribose) polymerase (PARP) under oxidative stress induces cytoskeletal disruption in vascular endothelial cell.

Vascular endothelial cytoskeletal disruption leads to increased vascular permeability and is involved in the pathogenesis and progression of various diseases. Oxidative stress can increase vascular permeability by weakening endothelial cell-to-cell junctions and decrease intracellular nicotinamide adenine dinucleotide (NAD ⁺ ) levels. However, it remains unclear how intracellular NAD ⁺ variations caused by oxidative stress alter the vascular endothelial cytoskeletal organization. In this study, we demonstrated that oxidative stress activates poly (ADP-ribose [ADPr]) polymerase (PARP), which consume large amounts of intracellular NAD ⁺ , leading to cytoskeletal disruption in vascular endothelial cells. We found that hydrogen peroxide (H ₂ O ₂ ) could transiently disrupt the cytoskeleton and reduce intracellular total NAD levels in human umbilical vein endothelial cells (HUVECs). H ₂ O ₂ stimulation led to rapid increase in ADPr protein levels in HUVECs. Pharmaceutical PARP inhibition counteracted H ₂ O ₂ -induced total NAD depletion and cytoskeletal disruption, suggesting that NAD ⁺ consumption by PARP induced cytoskeletal disruption. Additionally, supplementation with nicotinamide mononucleotide (NMN), the NAD ⁺ precursor, prevented both intracellular total NAD depletion and cytoskeletal disruption induced by H ₂ O ₂ in HUVECs. Inhibition of the NAD ⁺ salvage pathway by FK866, a nicotinamide phosphoribosyltransferase inhibitor, maintained H ₂ O ₂ -induced cytoskeletal disruption, suggesting that intracellular NAD ⁺ plays a crucial role in recovery from cytoskeletal disruption. Our findings provide further insights into the potential application of PARP inhibition and NMN supplementation for the treatment and prevention of diseases involving vascular hyperpermeability.
Competing Interests: Declaration of competing interest The authors state no conflict of interest.
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