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1α,25-Dihydroxyvitamin D3 Reverses Nitric Oxide and Peroxynitrite Imbalance in Dysfunctional Endothelium: A Nanomedical Approach

Khan, Alamzeb
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1439899541

Abstract Details

2015, Doctor of Philosophy (PhD), Ohio University, Chemistry and Biochemistry (Arts and Sciences).
Hypertension can be triggered by abnormal concentration of angiotensin-II; and diabetes mellitus is induced by hyperglycemia. Both hypertension and diabetes mellitus show adverse effects on endothelial function. Dysfunctional endothelium may produce less bioavailable NO and high level of oxidative stress. We hypothesized that endothelial dysfunction may be reversed by 1α,25-Dihydroxyvitamin D3. Using nanomedical methods and techniques we elucidated a multifunctional effect of 1α,25-Dihydroxyvitamin D3 on dysfunctional endothelium in cellular model of hypertension and diabetes mellitus. 1α,25-Dihydroxyvitamin D3 increased NO bioavailability and reduced nitroxidative stress by coupling eNOS dimer and downregulating expression of NADPH oxidase 4, eNOS, and iNOS in cultured HUVEC’s. NO and ONOO- concentrations were measured in near real-time with nanosensors in HUVEC’s of Caucasian American (CA) and African American (AA). ELISA was performed to measure the expression of eNOS, iNOS and NADPH oxidase 4 in HUVEC’s of CA and AA. Exposure of HUVEC’s to elevated concentration of angiotensin-II [1 µmol/L] and D-glucose [250 mg/dL] for 1-4 hours caused endothelial cells dysfunction manifested by eNOS uncoupling, reduced NO bioavailability and increased ONOO- concentration. Both angiotensin-II and D-glucose upregulated eNOS, iNOS and NADPH oxidase 4 expression level in HUVEC’s of both ethnic groups. 1α,25-Dihydroxyvitamin D3-treatments of dysfunctional HUVEC’s reduced eNOS, iNOS and NADPH oxidase 4 expression levels followed by significant reduction in ONOO- release and induction in NO bioavailability indicating that NADPH oxidase 4 plays a major role in endothelial dysfunction. The NADPH oxidase 4 role in endothelium dysfunction was confirmed by the use of NADPH oxidase inhibitor, VAS2870 [10 µmol/L]. VAS2870 increased NO bioavailability and reduced ONOO- release. The ratio of NO to ONOO- concentrations, [NO]/[ONOO-], was used as an indicator of eNOS coupling/uncoupling and endothelial function/dysfunction. The drop in the [NO]/[ONOO-] level below 1.0 indicates a severe eNOS uncoupling and severe endothelial dysfunction. The [NO]/[ONOO-] in fully functional endothelium was 2.50±0.09 for CA and 1.70±0.12 for AA. This [NO]/[ONOO-] decreased to 0.18±0.12 and to 0.11±0.9 in CA and AA after incubating HUVEC’s with angiotensin-II. HUVEC’s incubated with high dose of D-glucose, the [NO]/[ONOO-] balance dropped to 0.73±0.22 and 0.52±0.16 in CA and AA respectively. The uncoupling of eNOS was more severe in AA than in CA. The present study suggests that 1α,25-Dihydroxyvitamin D3 partially but significantly restored endothelial function. It improved NO bioavailability and reduced ONOO- concentration in HUVEC’s of CA and AA. 1α,25-Dihydroxyvitamin D3 improved the [NO]/[ONOO-] in both the angiotensin II and glucose-induced endothelial dysfunction. The beneficial effect 1α,25-Dihydroxyvitamin D3 on endothelial function was clearly associated with a decrease in the overexpression of eNOS, iNOS and NADPH oxidase 4.
Tadeusz Malinski (Advisor)
240 p.
Biochemistry
1a,25-Dihydroxyvitamin D3; Nitric oxide and Peroxynitrite Imbalance; Dysfunctional Endothelium; Endothelial Nitric Oxide Synthase Uncoupling and Endothelial Dysfunction; Oxidative and Nitroxidative Stress and Endothelial Dysfunction

Recommended Citations

Citations

  • Khan, A. (2015). 1α,25-Dihydroxyvitamin D3 Reverses Nitric Oxide and Peroxynitrite Imbalance in Dysfunctional Endothelium: A Nanomedical Approach [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1439899541

    APA Style (7th edition)

  • Khan, Alamzeb. 1α,25-Dihydroxyvitamin D3 Reverses Nitric Oxide and Peroxynitrite Imbalance in Dysfunctional Endothelium: A Nanomedical Approach. 2015. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1439899541.

    MLA Style (8th edition)

  • Khan, Alamzeb. "1α,25-Dihydroxyvitamin D3 Reverses Nitric Oxide and Peroxynitrite Imbalance in Dysfunctional Endothelium: A Nanomedical Approach." Doctoral dissertation, Ohio University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1439899541

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Ohio University and OhioLINK.