Characterizing CD38 Expression and Enzymatic Activity in the Brain of Spontaneously Hypertensive Stroke-Prone Rats

Yousef Hannawi; Mohamed G Ewees; Jordan T Moore; Jay L Zweier

doi:10.3389/fphar.2022.881708

Characterizing CD38 Expression and Enzymatic Activity in the Brain of Spontaneously Hypertensive Stroke-Prone Rats

Front Pharmacol. 2022 May 31:13:881708. doi: 10.3389/fphar.2022.881708. eCollection 2022.

Authors

Yousef Hannawi¹, Mohamed G Ewees^{2

3}, Jordan T Moore⁴, Jay L Zweier²

Affiliations

¹ Division of Cerebrovascular Diseases and Neurocritical Care, Department of Neurology, The Ohio State University, Columbus, OH, United States.
² Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States.
³ Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
⁴ Department of Biomedical Engineering, The Ohio State University, Columbus, OH, United States.

Abstract

Background: CD38 is a transmembrane glycoprotein that catabolizes nicotinamide adenine dinucleotide (NAD⁺) and is the main source for the age-dependent decrease in NAD⁺ levels. Increased CD38 enzymatic activity has been implicated in several neurological diseases. However, its role in the pathogenesis of cerebral small vessel disease (CSVD) remains unknown. We aimed to characterize CD38 expression and enzymatic activity in the brain of spontaneously hypertensive stroke-prone rats (SHRSP), a genetic model for hypertension and human CSVD, in comparison to age-matched normotensive Wistar Kyoto rats (WKY). Materials and Methods: Age-matched male 7- and 24-week-old WKY and SHRSP were studied. CD38 enzymatic activity was determined in the brain homogenate. Immunohistochemistry and Western Blotting (WB) were used to characterize CD38 expression and localize it in the different cell types within the brain. In addition, expression of nitric oxide synthase (NOS) isoforms and the levels of nitric oxide (NO), superoxide, nicotinamide dinucleotide (phosphate) NAD(P)H were measured the brain of in WKY and SHRSP. Results: CD38 expression and enzymatic activity were increased in SHRSP brains compared to age matched WKY starting at 7 weeks of age. CD38 expression was localized to the endothelial cells, astrocytes, and microglia. We also identified increased CD38 expression using WB with age in SHRSP and WKY. CD38 enzymatic activity was also increased in 24-week SHRSP compared to 7-week SHRSP. In association, we identified evidence of oxidative stress, reduced NO level, reduced NAD(P)H level and endothelial NOS expression in SHRSP compared to age matched WKY. NAD(P)H also decreased with age in WKY and SHRSP. Additionally, activation of astrocytes and microglia were present in SHRSP compared to WKY. Conclusions: CD38 is overexpressed, and its enzymatic activity is increased in SHRSP, a genetic model for marked hypertension and human CSVD. Our results suggest a potential role for CD38 enzymatic activation in the pathogenesis of CSVD and points to the need for future mechanistic and pharmacological studies.

Keywords: cerebral small vessel disease; hypertension; nitric oxide; nitric oxide synthase; oxidative stress; spontaneously hypertensive stroke prone rat.

Abstract

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