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

Abstract

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.

Altered Bioavailability of Nitric Oxide and L-Arginine Is a Key Determinant of Endothelial Dysfunction in Preeclampsia

“…In agreement with this study, Noris and his colleagues [ 38 ] demonstrated an excess formation of ONOO − in a preeclamptic placenta. ONOO − formation does not only inactivate NO ∙ but also leads to uncoupling of eNOS [ 39 ]. Uncoupled eNOS generates O 2 ·− rather than NO ∙ [ 40 ].…”

Novel antihypertensive action of rutin is mediated via inhibition of angiotensin converting enzyme/mineralocorticoid receptor/angiotensin 2 type 1 receptor (ATR1) signaling pathways in uninephrectomized hypertensive rats

“…The capacity of rutin to reduce the AOPP level was highly comparable to that of lisinopril. The inhibition of eNOS with production of peroxynitrite (ONOO‐) which is a cytotoxic molecule could also aggravate the formation of AOPP, thereby fostering endothelial damage and ultimate cardiovascular system compromise (Khan et al., 2018). The production of ONOO‐ is from the reaction between the superoxide anion radical (O 2 • ‐ ) and NO, with concomitant reduction in the NO bioavailability, thereby precipitating hypertension.…”

Progressive LDL Reduction to Very Low Levels Improves Dimeric Nitric Oxide Synthase, Nitric Oxide Bioavailability and Reduces Peroxynitrite in Endothelial Cells during Hyperglycemia

“…If [NO]/[ONOO -] falls below 0.5, it produces a severe oxidative stress that contributes to mechanisms of disease. 24 We found that it is not the absolute level of NO or ONOO -, but the ratio between them that is the determinant of the cellular redox environment (Burewicz et al, 2013;Mason et al, 2015;Khan et al, 2018;Sambe et al, 2018).…”