Introduction: CD38 is a multifunctional enzyme that plays a central role in NAD+ metabolism. Emerging evidence implicates it in oxidative stress injury and endothelial cells (ECs) dysfunction. We hypothesized that angiotensin-II (Ang-II) induced hypertension (HTN) upregulates CD38 in the brain ECs contributing to cerebrovascular oxidative injury. Methods: The early changes of CD38 expression and activity in response to Ang-II were resolved in vitro in a model of human brain primary microvascular endothelial cells (HBPMECs). CD38 loss of function effect was assessed by CD38 silencing siRNA. We measured CD38 expression by immunofluorescence (IF) and western blotting, enzymatic activity, superoxide (DHE- Dihydroethidium) generation, NAD(P)H level, and nitric oxide (NO) (DAF-diaminofluorescein) level. CD38 expression in vivo was examined in (10-13) week-old male C57BL/6J mice using Ang-II (non-pressor dose: 100 ng/kg/min or slow pressor dose: 600 ng/kg/min) and control saline delivered by subcutaneous miniosmotic pumps (N=16). Results: HBPMECs treatment with Ang-II rapidly increased CD38 enzymatic function within 5 min by 38% (p=0.035) which was accompanied by 31% NAD(P)H decrease (p=0.001). A 2.4-fold increase in CD38 expression was found after 120 min of Ang-II exposure (p<0.001). Superoxide generation increased at 5 min and reached a 5.5-fold maximum at 30 min (p<0.001) while NO declined by 24% starting at 15 min (p<0.001). CD38 knockdown in HBPMECs abolished the Ang-II–induced superoxide elevation, preserved NAD(P)H, and prevented NO loss. At 100 ng/kg/min of Ang-II, which did not significantly raise blood pressure or change total CD38 brain expression, CD38 was upregulated mainly in the ECs (of total CD38 by IF: 80% ECs and 20% astrocytes). Slow-pressor Ang-II which induces HTN and breaks the blood brain barrier, raised CD38 expression by 173% (p=0.004), and activity by 174% (p=0.03) in the total brain. At this dose, CD38 expression started to involve the perivascular astrocytes (of CD38 by IF: 70% ECs and 30% astrocytes). Ang-II induced HTN increased superoxide generation by 326% (p=0.01), reduced NO by 32% (p=0.022) and NAD(P)H by 26% (p<0.001) in the brain. Conclusions: The brain endothelial CD38 expression and activity are sensitive to Ang-II induced HTN while the loss of endothelial CD38 function protects against Ang-II mediated ECs oxidative injury. Targeting CD38 may represent a therapeutic strategy for HTN-induced cerebrovascular diseases.
Ewees et al. (Thu,) studied this question.
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