Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibition Improves Coronary Arteriole Function in Type 2 Diabetes

Type 2 diabetes (T2D) is associated with microvascular dysfunction. We hypothesized that increased Poly (ADP-ribose) polymerase-1 (PARP-1) activity contributes to microvascular dysfunction in T2D. T2D (db-/db-) and non-diabetic control (db-/db+) mice were treated with two different PARP-1 inhibitors (INO-1001, 5 mg/Kg/day and ABT-888, 15 mg/Kg/day) for two weeks. Isolated coronary arterioles (CA) were mounted in an arteriograph. Pressure-induced myogenic tone (MT) was significantly potentiated, while endothelium-dependent relaxation (EDR) was significantly attenuated in diabetic mice compared to control. These results were associated with decreased endothelial nitric oxide synthase (eNOS) phosphorylation, cyclic guanosine 3’ 5’-monophosphate (cGMP) level and increased PARP-1 activity in CA from diabetic mice compared to control. Interestingly, PARP-1 inhibitors significantly reduced the potentiation of MT, improved EDR, restored eNOS phosphorylation, cGMP and attenuated cleaved PARP-1. These results were supported by in vitro studies indicating that down-regulation of PARP-1 in mesenteric resistance arteries (MRA) using PARP-1 shRNA lenti-viral particles significantly improved EDR in MRA from diabetic mice compared to control. The inhibition of nitric oxide synthesis by N G-nitro-L-arginine methyl ester (L-NAME) significantly reduced the EDR in CA and MRA from control and diabetic mice treated with PARP-1 inhibitors and PARP-1 shRNA lenti-viral particles. In addition, we demonstrated that enhanced cleaved PARP-1, its binding to DNA and DNA damage were reduced after PARP-1 inhibition in cultured endothelial cells stimulated with high glucose. We provide evidence that T2D impairs microvascular function by an enhanced PARP-1 activity-dependent mechanism. Therefore, PARP-1 could be a potential target for overcoming diabetic microvascular complications.

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