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

BACKGROUND

Clinical studies indicate that vitamin D improves circulation and may have beneficial effects in hypertension. This study uses nanomedical systems to investigate the role of 1,25-dihydroxy vitamin D in the preservation/restoration of endothelial function in an angiotensin II (Ang II) cellular model of hypertension.

METHODS

1,25-dihydroxy vitamin D-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 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 restored uncoupled eNOS and endothelial function by increasing cytoprotective NO and decreasing the cytotoxic ONOO. The beneficial effect of vitamin D 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 may prove to be beneficial in the treatment of hypertension and other cardiovascular diseases, including heart failure, myocardial infarction, vasculopathy, stroke and diabetes.