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

Abstract

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.

Enhanced p22phoxexpression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice

“…We and other investigators showed an increase in myogenic tone in type 2 diabetes (12,25). In this study we demonstrated that in type 2 diabetic mice, elevated myogenic response is a consequence of enhanced p22 phox expression since the downregulation of p22 phox by siRNA and ROS scavenger restored the myogenic tone in diabetic mice.…”

“…The vessels were pressurized to 50 mmHg using pressureservo control perfusion system (Living Systems Instruments, St. Albans, VT) for a 40-min equilibration period. The vessel diameter was monitored by a video image analyzer as previously described (9,12).…”

Inhibition of endoplasmic reticulum stress improves coronary artery function in type 2 diabetic mice

“…The myogenic response is characterized by vasoconstriction in response to an increase of intraluminal pressure and vasodilatation in response to a decrease in intraluminal pressure and is an intrinsic vascular response that plays an important role in the local regulation of blood flow (Bayliss, 1902). Previous studies have shown that impaired small artery function is attributable to the enhanced myogenic response in diabetic animals (Lagaud et al 2001;Choi et al 2012;Kassan et al 2013). Interestingly, in the present study, we observed an enhanced myogenic response in the coronary arteries of type 2 diabetic mice associated with increased ER stress markers.…”

Glucagon-Like Peptide 1 Protects against Hyperglycemic-Induced Endothelial-to-Mesenchymal Transition and Improves Myocardial Dysfunction by Suppressing Poly(ADP-Ribose) Polymerase 1 Activity

“…PARP-1, the DNA repair-associated nuclear enzyme, is involved in the development of various diabetic complications, including diabetic cardiomyopathy, diabetic nephropathy, diabetic cystopathy and diabetic retinopathy (23,34,35). Hyperglycemia can lead to overproduction of mitochondrial ROS, which then activates PARP-1 (13).…”