Introduction: Essential hypertension involves an elevated systolic or diastolic blood pressure, usually greater than mmHg, that is not caused by secondary factors such as underlying disease1,4. Angiotensin II plays a major role in the development of essential hypertension by increasing the fluid volume in the blood due to salt reuptake by the kidneys2,5. Overtime, the vascular smooth muscle cells can change in response to angiotensin II-induced NOX1 expression, which promotes oxidative stress through the creation of reactive oxygen species. This can lead to inflammation and chronic hypertension2,5. Studies have shown that reactive oxygen species can hyperoxidize proteins which can lead to endoplasmic reticulum stress, and cellular senescence6,8. In addition, reactive oxygen species can suppress T-type Ca2+ channels, and cause early and late inflammatory responses 7,9. Further insight into T-type Ca2+ suppression as well as early and late inflammatory response may help in understanding the role of NOX1 in essential hypertension. Methods: Human umbilical vein endothelial cells (HUVECs) and cerebral arterial smooth muscle cells were utilized. HUVECs were treated with angiotensin II and western blot was used to determine NOX1 protein and inflammatory protein (IL-6, MCP-1, TNF-a) concentrations at different time intervals. Cerebral arterial smooth muscle cells were treated with angiotensin II and NOX1 inhibitors (apocynin & ML-171), followed by the measurement of current density flowing through T-type Ca2+ channels using a patch-clamp amplifier. Results: Angiotensin II-induced NOX1 expression caused a peak increase in inflammatory proteins at 4 hours in HUVECs, which was associated with the peak increase of NOX1 protein levels. In cerebral arterial smooth muscle cells, angiotensin II caused a decrease in current flow through T-type Ca2+ channels; however, the current flow returned to normal after the administration of NOX1 inhibitors. Discussion: These findings show that NOX1 levels fluctuate throughout the day and cause high levels of inflammation at different time intervals9. In addition, NOX1 proteins decrease the flow of current in T-type Ca2+ channels7. The decrease in current prevents hyperpolarization of cerebral arterial smooth muscle cells by decreasing BKCa activity7. Although L-type Ca2+ channels are primarily involved in vasoconstriction, T-type Ca2+ channels help modulate disproportionate narrowing of blood vessels through BKCa activity, which causes hyperpolarization of smooth muscle and vessel relaxation7. Angiotensin II-induced NOX1 expression can cause oxidative stress which may lead to essential hypertension through excess vasoconstriction and inflammation.
- Cuevas S, Villar VAM, Jose PA. Genetic polymorphisms associated with reactive oxygen species and blood pressure regulation. The Pharmacogenomics Journal. December 2018. doi:10.1038/s41397-019-0082-4.
- Das S, Zhang E, Senapati P, et al. A Novel Angiotensin II–Induced Long Noncoding RNA Giver Regulates Oxidative Stress, Inflammation, and Proliferation in Vascular Smooth Muscle Cells. Circulation Research. 2018;123(12):1298-1312. doi:10.1161/circresaha.118.313207
- García-Redondo AB, Aguado A, Briones AM, Salaices M. NADPH oxidases and vascular remodeling in cardiovascular diseases. Pharmacological Research. 2016;114:110-120. doi:10.1016/j.phrs.2016.10.015.
- Garfinkle MA. Salt and essential hypertension: pathophysiology and implications for treatment. Journal of the American Society of Hypertension. 2017;11(6):385-391. doi:10.1016/j.jash.2017.04.006.
- Masi S, Uliana M, Virdis A. Angiotensin II and vascular damage in hypertension: Role of oxidative stress and sympathetic activation. Vascular Pharmacology. 2018;01(004). doi:10.1016/j.vph.2019.01.004.
- Camargo, L. L., Harvey, A. P., Rios, F. J., Tsiropoulou, S., Renée De Nazaré Oliveira Da Silva, Cao, Z., . . . Touyz, R. M. (2018). Vascular Nox (NADPH Oxidase) Compartmentalization, Protein Hyperoxidation, and Endoplasmic Reticulum Stress Response in Hypertension. Hypertension,72(1), 235-246. doi:10.1161/hypertensionaha.118.10824
- Hashad, A. M., Sancho, M., Brett, S. E., & Welsh, D. G. (2018). Reactive Oxygen Species Mediate the Suppression of Arterial Smooth Muscle T-type Ca2 Channels by Angiotensin II. Scientific Reports,8(1). doi:10.1038/s41598-018-21899-5
- Tsai, I., Pan, Z., Cheng, H., Liu, C., Lin, B., & Jiang, M. J. (2016). Reactive oxygen species derived from NADPH oxidase 1 and mitochondria mediate angiotensin II-induced smooth muscle cell senescence. Journal of Molecular and Cellular Cardiology,98, 18-27. doi:10.1016/j.yjmcc.2016.07.001
- Zhang, X., Yang, J., Yu, X., Cheng, S., Gan, H., & Xia, Y. (2016). Angiotensin II-Induced Early and Late Inflammatory Responses Through NOXs and MAPK Pathways. Inflammation,40(1), 154-165. doi:10.1007/s10753-016-0464-6