Nanomedical studies of the restoration of nitric oxide/peroxynitrite balance in dysfunctional endothelium by 1,25-dihydroxy vitamin D(3) – 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.