Estrogen-dependent hypersensitivity to diabetes-evoked cardiac autonomic dysregulation: Role of hypothalamic neuroinflammation.

Abstract

AIMS:

To investigate if autonomic dysregulation is exacerbated in female rats, subjected to diabetes mellitus (DM), via a paradoxical estrogen (E2)-evoked provocation of neuroinflammation/injury of the hypothalamic paraventricular nucleus (PVN).

MAIN METHODS:

We measured cardiac autonomic function and conducted subsequent PVN neurochemical studies, in DM rats, and their respective controls, divided as follows: male, sham operated (SO), ovariectomized (OVX), and OVX with E2 supplementation (OVX/E2).

KEY FINDINGS:

Autonomic dysregulation, expressed as sympathetic dominance (higher low frequency, LF, band), only occurred in DM E2-replete (SO and OVX/E2) rats, and was associated with higher neuronal activity (c-Fos) and higher levels of TNFα and phosphorylated death associated protein kinase-3 (p-DAPK3) in the PVN. These proinflammatory molecules likely contributed to the heightened PVN oxidative stress, injury and apoptosis. The PVN of these E2-replete DM rats also exhibited upregulations of estrogen receptors, ERα and ERβ, and proinflammatory adenosine A1 and A2a receptors.

SIGNIFICANCE:

The E2-dependent autonomic dysregulation likely predisposes DM female rats and women to hypersensitivity to cardiac dysfunction. Further, upregulations of proinflammatory mediators including adenosine A1 and A2 receptors, TNFα and DAPK3, conceivably explain the paradoxical hypersensitivity of DM females to PVN inflammation/injury and the subsequent autonomic dysregulation in the presence of E2.

• Authors: Mohamed A Fouda, Korin E Leffler, Abdel A Abdel-Rahman
• Journal: Life sciences (Life Sci) Vol. 250 Pg. 117598 (Jun 01 2020) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 32243927 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Estrogens
• Reactive Oxygen Species
• Receptor, Adenosine A1
• Receptor, Adenosine A2A
• Tumor Necrosis Factor-alpha
• Dapk3 protein, rat
• Death-Associated Protein Kinases

Topics

• Animals
• Apoptosis
• Autonomic Nervous System (physiopathology)
• Death-Associated Protein Kinases (metabolism)
• Diabetes Complications (physiopathology)
• Diabetes Mellitus, Experimental (complications)
• Estrogens (pharmacology)
• Female
• Heart (drug effects)
• Heart Diseases (physiopathology)
• Heart Rate
• Hypothalamus (physiopathology)
• Inflammation (pathology)
• Male
• Oxidative Stress
• Paraventricular Hypothalamic Nucleus (metabolism)
• Phosphorylation
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Receptor, Adenosine A1 (metabolism)
• Receptor, Adenosine A2A (metabolism)
• Sex Factors
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation