Regulator of G-Protein Signaling 5 Protein Deficiency Differentially Influences Blood Pressure, Vascular and Behavioral Effects in Aged Male Mice.

ABSTRACT: Aging and elevated activity of the renin-angiotensin-system (RAS) are associated with hypertension, vascular and emotional behavioral abnormalities, like anxiety and depression. Many actions of the main effector hormone of the RAS, angiotensin II (Ang II), are mediated by Ang II type 1 receptor whose activity is modulated by the regulator of G-protein signaling 5 (RGS5) protein. We assessed the role of RGS5 on blood pressure, vascular and emotional behavioral outcomes in aged male mice in the presence and absence of chronically elevated Ang II levels. We used aged (∼21-month old) male RGS5-deficient (RGS5 -/- ) and wild-type (RGS5 +/+ ) mice treated with vehicle (saline) or Ang II (1 mg/kg/d for 21 days). RGS5 deficiency increased baseline and cerebral vascular superoxide levels in the presence of chronically elevated Ang II levels, suggesting that RGS5 deficiency leads to elevated blood pressure and deleterious cerebral vascular outcomes in aged mice. RGS5 deletion had no effect on Ang II-induced increases in systolic blood pressure. Chronically elevated Ang II levels increased spontaneous locomotor activity in RGS5 +/+ but not RGS5 -/- mice. RGS5 deficiency and Ang II treatment had no effect on anxiety- and depression-like behavior. This is the first study to assess the effects of deficiency of an RGS protein in the vasculature or on emotional behavioral outcomes in aged mice. We report that RGS5 has protective effects on blood pressure and the cerebral vasculature in aged mice. Clinically, these data suggest that RAS blockers may significantly reduce cerebrovascular disease risk in aged males lacking RGS5.

Targeting the renin angiotensin system for the treatment of anxiety and depression.

Emotional disorders like anxiety and depression are responsible for considerable morbidity and mortality all over the world. Several antidepressant and anxiolytic medications are available for the treatment of anxiety and depression. However, a significant number of patients either do not respond to these medications or respond inadequately. Hence, there is a need to identify novel targets for the treatment of anxiety and depression. In this review we focus on the renin angiotensin system (RAS) as a potential target for the treatment of these disorders. We review work that has evaluated the effects of various compounds targeting the RAS on anxiety- and depression-like behaviors. Further, we suggest future work that must be carried out to fully exploit the RAS for the treatment of anxiety and depression. The RAS provides an attractive target for both the identification of novel anxiolytic and antidepressant medications and/or for enhancing the efficacy of currently available medications used for the treatment of anxiety and depression.