Nanomedical studies of the restoration of nitric oxide/peroxynitrite balance in dysfunctional endothelium by 1,25-dihydroxy vitamin D3-clinical implications for cardiovascular diseases

Background: Clinical studies indicate that vitamin D-3 improves circulation and may have beneficial effects in hypertension. This study uses nanomedical systems to investigate the role of 1,25-dihydroxy vitamin D-3 in the preservation/restoration of endothelial function in an angiotensin II (Ang II) cellular model of hypertension. Methods: 1,25-dihydroxy vitamin D-3-stimulated nitric oxide (NO) and peroxynitrite (ONOO-) concentrations were measured in situ with nanosensors (200-300 mm diameter with a detection limit of 1 nM) in human umbilical vein endothelial cells of African American (AA) and Caucasian American (CA) donors exposed to Ang II. The balance/imbalance between NO and ONOO-concentrations ([NO]/[ONOO-]) was simultaneously monitored and used as an indicator of endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction. Results: [NO]/[ONOO-] imbalance in Ang II-stimulated dysfunctional endothelium was 0.20 +/- 0.16 for CAs and 0.11 +/- 0.09 for AAs. Uncoupled eNOS and overexpression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contributed to high production of ONOO-. Vitamin D-3 treatment reversed [NO]/[ONOO-] to 3.0 +/- 0.1 in CAs and 2.1 +/- 0.1 in AAs -exceeding that observed in normal endothelium. Vitamin D-3 restored uncoupled eNOS and endothelial function by increasing cytoprotective NO and decreasing the cytotoxic ONOO-. The beneficial effect of vitamin D-3 is associated with a favorable rate of NO and ONOO-release, restoration of the [NO]/[ONOO-] and the overall decrease in the overexpression of eNOS, inducible nitric oxide synthase and NADPH oxidase. This effect of vitamin D-3 may prove to be beneficial in the treatment of hypertension and other cardiovascular diseases, including heart failure, myocardial infarction, vasculopathy, stroke and diabetes.