Regulatory Mechanisms in Biosystems (Jun 2023)

Downregulation of SIRT1, SIRT3, and IGF-1 in ApoE-deficient mice exacerbates neuronal damage induced by chronic cerebral hypoperfusion

  • O. Y. Harmatina,
  • K. V. Rozova,
  • T. Y. Voznesenska,
  • M. I. Vasylenko,
  • T. Y. Lapikova-Bryhinska,
  • A. G. Portnychenko

DOI
https://doi.org/10.15421/10.15421/022350
Journal volume & issue
Vol. 14, no. 3
pp. 341 – 348

Abstract

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Chronic cerebral hypoperfusion is a widespread pathological condition caused by chronically reduced cerebral blood flow leading to brain damage, but the specific molecular mechanisms that regulate these phenomena remain poorly understood. In this study, we investigated brain damage and neuronal DNA injury in a vulnerable region of the brain, the hippocampus, as well as the involvement of apolipoprotein E (ApoE), sirtuins of 1 (SIRT1) and 3 (SIRT3) types and insulin-like growth factor 1 (IGF-1) in pathogenetic mechanisms in mice with chronic cerebral hypoperfusion caused by the permanent occlusion of the left unilateral common carotid artery. Male C57/6j (C57, wild type) and ApoE(-/-) mice were divided into four experimental groups (10 mice per group): sham-operated С57, С57 with chronic cerebral hypoperfusion, sham-operated ApoE(-/-) mice, ApoE(-/-) mice with chronic cerebral hypoperfusion. Our results showed that the number of damaged neurons in the hippocampus at 8 weeks after surgical manipulation increased in both groups of mice with chronic cerebral hypoperfusion, with more pronounced rates in ApoE(-/-) mice than in C57 mice. However, ApoE deficiency in moderate chronic cerebral hypoperfusion was accompanied by a higher level of undamaged DNA (class 0) and a low level of maximally damaged DNA (class 4) in brain cell nuclei in contrast to group C57. In ApoE-deficient mice, reduced expression of SIRT1, SIRT3, and IGF-1 was found. In chronic cerebral hypoperfusion, expression of sirtuins was preserved, but IGF-1 expression was significantly reduced in ApoE(-/-) mice in comparison to C57. The obtained results indicate that ApoE deficiency leads to downregulation of SIRT1, SIRT3 and IGF-1 in the brain; this lack of cytoprotection is enhanced in chronic cerebral hypoperfusion and may participate in the mechanisms of neuronal damage.

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