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Poly(ADP-ribose) polymerase 1 inhibition improves coronary arteriole function in type 2 diabetes mellitus

 Soo-Kyoung Choi  ;  Maria Galán  ;  Modar Kassan  ;  Megan Partyka  ;  Mohamed Trebak  ;  Khalid Matrougui 
 HYPERTENSION, Vol.59(5) : 1060-1068, 2012 
Journal Title
Issue Date
Animals ; Benzimidazoles/pharmacology ; Blood Glucose/analysis ; Blood Pressure Determination ; Blotting, Western ; Body Weight ; Coronary Vessels/drug effects* ; Coronary Vessels/enzymology* ; Coronary Vessels/pathology ; Diabetes Mellitus, Type 2/drug therapy* ; Diabetes Mellitus, Type 2/enzymology* ; Diabetic Angiopathies/drug therapy* ; Diabetic Angiopathies/enzymology* ; Diabetic Angiopathies/physiopathology ; Disease Models, Animal ; Down-Regulation ; Immunohistochemistry ; Indoles/pharmacology ; Insulin Resistance/physiology ; Mice ; Mice, Inbred Strains ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerase Inhibitors* ; Polymerase Chain Reaction/methods ; Random Allocation ; Sensitivity and Specificity
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.
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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Choi, Soo Kyoung(최수경) ORCID logo https://orcid.org/0000-0002-7115-6358
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