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. 2024 Apr;44(4):556-572.
doi: 10.1177/0271678X231212961. Epub 2023 Nov 9.

Acute severe hypoglycemia alters mouse brain microvascular proteome

Siva Svp Sakamuri  1 , Venkata N Sure  1 , Lokanatha Oruganti  1 , William Wisen  1 , Partha K Chandra  1   2 , Ning Liu  2   3   4 , Vivian A Fonseca  1   5 , Xiaoying Wang  2   3   4 , Jennifer Klein  6 , Prasad Vg Katakam  1   2   3
Affiliations

Acute severe hypoglycemia alters mouse brain microvascular proteome

Siva Svp Sakamuri et al. J Cereb Blood Flow Metab. 2024 Apr.

Abstract

Hypoglycemia increases the risk related to stroke and neurodegenerative diseases, however, the underlying mechanisms are unclear. For the first time, we studied the effect of a single episode (acute) of severe (ASH) and mild (AMH) hypoglycemia on mouse brain microvascular proteome. After four-hour fasting, insulin was administered (i.p) to lower mean blood glucose in mice and induce ∼30 minutes of ASH (∼30 mg/dL) or AMH (∼75 mg/dL), whereas a similar volume of saline was given to control mice (∼130 mg/dL). Blood glucose was allowed to recover over 60 minutes either spontaneously or by 20% dextrose administration (i.p). Twenty-four hours later, the brain microvessels (BMVs) were isolated, and tandem mass tag (TMT)-based quantitative proteomics was performed using liquid chromatography-mass spectrometry (LC/MS). When compared to control, ASH significantly downregulated 13 proteins (p ≤ 0.05) whereas 23 proteins showed a strong trend toward decrease (p ≤ 0.10). When compared to AMH, ASH significantly induced the expression of 35 proteins with 13 proteins showing an increasing trend. AMH downregulated only 3 proteins. ASH-induced downregulated proteins are involved in actin cytoskeleton maintenance needed for cell shape and migration which are critical for blood-brain barrier maintenance and angiogenesis. In contrast, ASH-induced upregulated proteins are RNA-binding proteins involved in RNA splicing, transport, and stability. Thus, ASH alters BMV proteomics to impair cytoskeletal integrity and RNA processing which are critical for cerebrovascular function.

Keywords: Brain microvessels; RNA splicing; actin cytoskeleton; insulin; proteomics.

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Conflict of interest statement

Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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