Title

Regulator of G-protein signaling 5 protein modulates blood pressure and cerebral vascular superoxide levels in aged mice

Document Type

Conference Proceeding

Publication Date

4-1-2019

Abstract

Aging is an independent cardiovascular risk factor that is associated with cerebral vascular abnormalities, and alterations in the incidence of emotional abnormalities such as anxiety and depression in aged males. The angiotensin II (Ang II) type 1 receptor (AT1R) is a G-protein coupled receptor whose activity may be modulated by regulator of G-protein signaling 5 (RGS5) protein. AT1R reportedly contributes to cerebral vascular dysfunction in aged mice, and excessive AT1R activation is associated with vulnerability to anxiety-like behavior. Furthermore, in humans, angiotensin converting enzyme inhibition was successful in treating major depression. In adult male mice, we have previously reported that a deficiency of RGS5 results in increased Ang II-induced depression-like behavior. In contrast, deficiency of RGS5 alone induced anxiety-like behavior, and RGS5 deficiency had no effect on cerebral vascular superoxide levels. However, the effect of RGS5 deficiency on blood pressure, cerebral vascular and emotional abnormalities in the absence and presence of elevated Ang II levels in aged male mice is unknown. Therefore, the aims of this study were to test whether RGS5 modulates blood pressure, cerebral vascular oxidative stress, and anxiety-and depression-like behavior in aged (16–20 month old) male mice in the absence and presence of elevated Ang II levels. Wild-type (RGS5+/+) and RGS5-deficient (RGS5−/−) mice were treated with Ang II (1 mg/kg/d) or vehicle (saline) for 21 days using osmotic minipumps. In this study, we assessed systolic blood pressure (SBP) using tail cuff, anxiety-like behavior using the elevated plus maze, depression-like behavior using the tail suspension test, and spontaneous locomotor activity using an automated apparatus equipped with photobeams, in conscious mice. Furthermore, we assessed oxidative stress using LO12 chemiluminesence in isolated cerebral arteries. RGS5 deficiency increased SBP under normal conditions (SBP in RGS5+/+ = 105 ± 5 mmHg, n = 24; RGS5−/− = 121 ± 5, mmHg, n = 19, P<0.05), suggesting that RGS5 deficiency leads to an increase in blood pressure during aging. RGS5 deficiency had no effect on the Ang II-induced increase in blood pressure. RGS5 deficiency increased cerebral vascular superoxide levels in the presence of elevated Ang II levels (superoxide levels in Ang II-treated RGS5+/+ = 459 ± 65 counts/s/mg, n = 8; Ang II-treated RGS5−/− = 1807 ± 600 counts/s/mg, n = 8, P<0.05). RGS5 deficiency and Ang II treatment had no effect on anxiety- and depression-like behavior, and spontaneous locomotor activity. In summary, these data suggest that during aging in males, RGS5 protects against elevated blood pressure. In addition, RGS5 protects against cerebral vascular oxidative stress in the presence of elevated Ang II levels during aging.

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