title: Poly(ADP-ribose) polymerase 1 inhibition improves coronary arteriole function in type 2 diabetes mellitus.
abstract: Type 2 diabetes mellitus (T2DM) is associated with microvascular dysfunction. We hypothesized that increased poly(ADP-ribose) polymerase 1 (PARP-1) activity contributes to microvascular dysfunction in T2DM. T2DM (db(-)/db(-)) and nondiabetic control (db(-)/db(+)) mice were treated with 2 different PARP-1 inhibitors (INO-1001, 5 mg/kg per day and ABT-888, 15 mg/kg per day) for 2 weeks. Isolated coronary arterioles were mounted in an arteriograph. Pressure-induced myogenic tone was significantly potentiated, whereas endothelium-dependent relaxation was significantly attenuated in diabetic mice compared with control mice. These results were associated with decreased endothelial NO synthase phosphorylation and cGMP level and increased PARP-1 activity in coronary arterioles from diabetic mice compared with control mice. Interestingly, PARP-1 inhibitors significantly reduced the potentiation of myogenic tone, improved endothelium-dependent relaxation, restored endothelial NO synthase phosphorylation and cGMP, and attenuated cleaved PARP-1. These results were supported by in vitro studies indicating that downregulation of PARP-1 in mesenteric resistance arteries using PARP-1 short hairpin RNA lentiviral particles significantly improved endothelium-dependent relaxation in mesenteric resistance arteries from diabetic mice compared with control mice. The inhibition of NO synthesis by N(G)-nitro-L-arginine methyl ester (L-NAME) significantly reduced the endothelium-dependent relaxation in coronary arterioles and mesenteric resistance arteries from control and diabetic mice treated with PARP-1 inhibitors and PARP-1 short hairpin RNA lentiviral 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 T2DM impairs microvascular function by an enhanced PARP-1 activity-dependent mechanism. Therefore, PARP-1 could be a potential target for overcoming diabetic microvascular complications.
authors.affiliation: Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Soo-Kyoung
authors.initials: SK
authors.lastname: Choi
authors.forename: Maria
authors.initials: M
authors.lastname: Galán
authors.forename: Modar
authors.initials: M
authors.lastname: Kassan
authors.forename: Megan
authors.initials: M
authors.lastname: Partyka
authors.forename: Mohamed
authors.initials: M
authors.lastname: Trebak
authors.forename: Khalid
authors.initials: K
authors.lastname: Matrougui
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D001795:Blood Pressure Determination; D015153:Blotting, Western; D001835:Body Weight; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016133:Polymerase Chain Reaction / Q000379:methods; D011897:Random Allocation; D012680:Sensitivity and Specificity
chemical_list: D001562:Benzimidazoles; D001786:Blood Glucose; C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1