Niacin improves ischemia-induced neovascularization in diabetic mice by enhancement of endothelial progenitor cell functions independent of changes in plasma lipids

Abstract

Niacin was shown to inhibit acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids. Here, we investigated whether niacin can increase blood flow recovery after tissue ischemia by enhancing endothelial progenitor cell (EPC) functions in diabetic mice. Starting at 4 weeks after the onset of diabetes, vehicle or niacin (40 mg/kg/day) was administered daily by gavage to streptozotocin (STZ)-induced diabetic mice and diabetic endothelial nitric oxide synthase (eNOS)-deficient mice. Unilateral hindlimb ischemia surgery was conducted after 2 weeks of vehicle or niacin treatment. Compared to the control group, the niacin group had significantly increased ischemic/non-ischemic limb blood perfusion ratio and higher capillary density. These effects were markedly reduced in STZ-induced diabetic eNOS-deficient mice. Flow cytometry analysis showed impaired EPC-like cell (Sca-1(+)/Flk-1(+)) mobilization after ischemia surgery in diabetic mice but augmented mobilization in the mice treated with niacin. Diabetes was induced by administering STZ to FVB mice that received eGFP mouse bone marrow cells to evaluate effects of niacin on bone marrow-derived EPC homing and differentiation to endothelial cells. Differentiation of bone marrow-derived EPCs to endothelial cells in the ischemic tissue around vessels in diabetic mice that received niacin treatment, was significantly increased than that in control group. By in vitro studies, incubation with niacin in high-glucose medium reduced H(2)O(2) production, cell apoptosis, and improved high glucose-suppressed EPC functions by nitric oxide-related mechanisms. Our findings demonstrate that niacin increases blood flow recovery after tissue ischemia in diabetic mice through enhancing EPC mobilization and functions via nitric oxide-related pathways.

Central GPR109A Activation Mediates Glutamate-Dependent Pressor Response in Conscious Rats

“…Therefore, It is likely that the increased levels of NO by NA (0.01-1mM) in PC12 cells (Fig. 6C) levels, which agrees with a reported finding in cultured endothelial cells treated with similar (0.5-2 mM) NA concentrations (Huang et al, 2012), is probably due to the activation of NMDAR, via GPR109A-mediated glutamate release. Notably, higher NO levels can contribute to RVLM oxidative stress via its interaction with elevated superoxide levels, detected by DHE staining in the RVLM of NA treated rats (Fig.…”

Niacin as antidyslipidemic drug

“…In experiments in diabetic mice the differentiation of bone marrow-derived endothelial progenitor cell (EPCs) into endothelial cells in the ischemic tissue around vessels that received niacin treatment was significantly increased compared to a control group (Huang et al 2012). By in vitro studies, an incubation with niacin in high-glucose medium reduced H 2 O 2 production, cell apoptosis, and improved high glucose-suppressed EPC functions by nitric oxide-related mechanisms (Huang et al 2012).…”

Expression of the Niacin Receptor GPR109A in Retina: More than Meets the Eye?

“…Support for this line of thought and therefore the therapeutic targeting of GPR109A in diabetic retina can be inferred from the recent report by Poplawski et al [44] demonstrating pronounced and effective reversal of parameters associated with progression and increased severity of diabetic nephropathy, another major complication of diabetes, through employment of a ketogenic diet, a diet in which β-hydroxybutyrate is the predominant ketone. Additional support can be gathered from a study by Huang et al [40] in which the authors report niacin-induced improvement of blood flow and peripheral vascular function in a diabetic rodent model of ischemia-reperfusion through mechanisms involving the modification of nitric oxide bioavailability and reduction of oxidative stress, and from clinical and experimental studies of neurodegenerative brain diseases touting the cellular protective effects of β-hydroxybutyrate when employed therapeutically [45].…”

“…However, fibrates and statins, well-known anti-hyperlipidemic agents, have been shown to reduce significantly the risk of advanced DR development and progression both in human patients and experimental models of disease [31][32][33][34][35]. There are an increasing number of new reports citing the benefits of niacin-GPR109A signaling in the treatment of pathologies other than hyperlipidemia (e.g., multiple sclerosis, septic shock, lung inflammation and fibrosis, renal failure, ischemia-induced neovascularization and peripheral vascular dysfunction in diabetes) [36][37][38][39][40]. This coupled with the fact that niacin, the prototypic GPR109A agonist, elicits additional, unique actions atop its lipid-lowering effects via its interaction with GPR109A raises the question as to whether similar or added benefit might be attained upon therapeutic targeting of the receptor in DR.…”