1. Pharmacological inhibition of histone deacetylase alleviates chronic unpredictable stress induced atherosclerosis and endothelial dysfunction via upregulation of BDNF.
- Author
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Rehman M, Agarwal V, Chaudhary R, Kaushik AS, Srivastava S, Srivastava S, Kumar A, Singh S, and Mishra V
- Subjects
- Animals, Male, Mice, Stress, Psychological complications, Stress, Psychological drug therapy, Stress, Psychological metabolism, Vascular Cell Adhesion Molecule-1 metabolism, Vascular Cell Adhesion Molecule-1 genetics, Nitric Oxide Synthase Type III metabolism, Endothelin-1 metabolism, Aorta, Thoracic metabolism, Aorta, Thoracic drug effects, Aorta, Thoracic pathology, Atherosclerosis metabolism, Atherosclerosis drug therapy, Atherosclerosis pathology, Brain-Derived Neurotrophic Factor metabolism, Brain-Derived Neurotrophic Factor genetics, Histone Deacetylase Inhibitors pharmacology, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Up-Regulation drug effects, Mice, Inbred C57BL, Valproic Acid pharmacology
- Abstract
Long-term stress is a significant risk factor for cardiovascular diseases, including atherosclerosis and endothelial dysfunction. Moreover, prolonged stress has shown to negatively regulate central BDNF expression. The role of central BDNF in CNS disorders is well studied until recently the peripheral BDNF was also found to be involved in endothelial function regulation and atherosclerosis. The peripheral BDNF and its role in chronic stress-induced atherosclerosis and endothelial dysfunction remain unclear. Therefore, we aimed to elucidate the role of BDNF and its modulation by the HDAC inhibitor valproic acid (VA) in chronic unpredictable stress (CUS)-induced atherosclerosis and endothelial dysfunction. We demonstrated that a 10-week CUS mouse model substantially decreases central and peripheral BDNF expression, resulting in enhanced serum lipid indices, plaque deposition, fibrosis, and CD68 expression in thoracic aortas. Further, parameters associated with endothelial dysfunction such as increased levels of endothelin-1 (ET-1), adhesion molecules like VCAM-1, M1 macrophage markers, and decreased M2 macrophage markers, eNOS expression, and nitrite levels in aortas, were also observed. VA (50 mg/kg, 14 days, i. p.) was administered to mice following 8 weeks of CUS exposure until the end of the experimental procedure. VA significantly prevented the decrease in BDNF, eNOS and nitrite levels, reduced lesion formation and fibrosis in thoracic aortas and increased ET-1, and VCAM-1 followed by M2 polarization in VA-treated mice. The study highlights the potential of epigenetic modulation of BDNF as a therapeutic target, in stress-induced cardiovascular pathologies and suggests that VA could be a promising agent for mitigating CUS-induced endothelial dysfunction and atherosclerosis by BDNF modulation., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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