Abstract Body: Introduction: CD38 is an ectoenzyme that is the main determinant of NAD⁺ level. We have shown that the brain CD38 expression and enzymatic activity are increased in the setting of hypertension (HTN) including spontaneously hypertensive stroke prone rat and angiotensin-II (Ang-II) induced HTN. Therefore, we aimed to characterize the effects of Ang-II administration dose and duration on the brain CD38 expression and enzymatic activity.
Methods: Male C57BL/6J mice (10-13) weeks (wks) of age (N=10) underwent subcutaneous infusion of Ang-II for a duration of 2-wks at (100 ng/kg/min or 600 ng/kg/min) or 6-wks (N=6) at 600 ng/kg/min through osmotic pumps. Control mice (N=10) underwent matching durations of saline infusion. CD38 enzymatic activity was measured by the NAD⁺ analogue conversion to the fluorescent product (ε-ADPR). CD38 expression was assessed by immunoblotting and immunofluorescence (IF). Amyloid beta (Aβ) and CD38 localization to the different brain cells were done by IF. Superoxide generation was measured using dihydroethidium (DHE).
Results: Ang-II infusion at 600 ng/kg/min caused a slow rise in systolic blood pressure (SBP) with sustained HTN by 2 wks (Ang-II: 151±6.5 vs saline: 110±4.3 mmHg, p=0.0007) and worsening HTN by 6 wks. 100 ng/kg/min of Ang-II did not significantly raise SBP and the brain expression of CD38 at this dose primarily localized to the vessels and endothelial cells (ECs). While CD38 was significantly expressed on ECs in the brain at 2 wks of 600 ng/kg/min of Ang-II, it was also seen on astrocytes and microglia. The expression pattern remained similar at 6 wks Ang-II infusion. Total brain CD38 expression and enzymatic activity were increased at 2 wks of 600 ng/kg/min Ang-II infusion and they remained elevated at similar levels at 6 wks Ang-II infusion. A 362% increase in superoxide was seen at 2 wks of 600 ng/kg/min Ang-II compared to that in control mice and remained similarly elevated at 6 wks Ang-II infusion. Aβ was 233% higher at 2 wks of 600 ng/kg/min of Ang-II and further increased with 6 wks of Ang-II infusion to 331% of levels in control mice.
Conclusions: Nonpressor dose of Ang-II primarily increases CD38 expression in the cerebral vessels and ECs. Higher Ang-II dose leading to HTN increases the brain CD38 expression and enzymatic activity with accompanied neuronal injury in prolonged Ang-II infusion. These results suggest CD38 as a potential target for improving HTN induced cerebrovascular dysfunction and brain health.