Angiotensin II–Mediated Neuroinflammation in the Hippocampus Contributes to Neuronal Deficits and Cognitive Impairment in Heart Failure Rats 2023

pattismith

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https://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.123.21070

Abstract​


Background:​

Heart failure (HF) is a debilitating disease affecting >64 million people worldwide. In addition to impaired cardiovascular performance and associated systemic complications, most patients with HF suffer from depression and substantial cognitive decline.
Although neuroinflammation and brain hypoperfusion occur in humans and rodents with HF, the underlying neuronal substrates, mechanisms, and their relative contribution to cognitive deficits in HF remains unknown.

Methods:​

To address this critical gap in our knowledge, we used a well-established HF rat model that mimics clinical outcomes observed in the human population, along with a multidisciplinary approach combining behavioral, electrophysiological, neuroanatomical, molecular and systemic physiological approaches.

Results:​

Our studies support neuroinflammation, hypoperfusion/hypoxia, and neuronal deficits in the hippocampus of HF rats, which correlated with the progression and severity of the disease. An increased expression of AT1aRs (Ang II [angiotensin II] receptor type 1a) in hippocampal microglia preceded the onset of neuroinflammation.

Importantly, blockade of AT1Rs with a clinically used therapeutic drug (Losartan), and delivered in a clinically relevant manner, efficiently reversed neuroinflammatory end points (but not hypoxia ones), resulting in turn in improved cognitive performance in HF rats. Finally, we show than circulating Ang II can leak and access the hippocampal parenchyma in HF rats, constituting a possible source of Ang II initiating the neuroinflammatory signaling cascade in HF.

Conclusions:​

In this study, we identified a neuronal substrate (hippocampus), a mechanism (Ang II–driven neuroinflammation) and a potential neuroprotective therapeutic target (AT1aRs) for the treatment of cognitive deficits in HF.
 

datadragon

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It has been described that All-trans retinoic acid (atRA) suppresses AT1R at both mRNA and protein levels. all trans retinoic acid, an active metabolite of Vitamin A, tends to inhibit several inflammatory reactions by suppressing NF-κB-mediated gene expression of IL-6, IL-1β, TNF-α, and MCP-1 in vitro and in vivo. Zinc is involved in Vitamin A metabolism as is Cytochrome P450 enzymes that require magnesium as a cofactor. AT1R inhibitors suppressed the expression of Angiotensin II and IL6, and directly blocked AT1R, thus avoiding STAT3 activation. Additionally, they suppress TNF-α synthesis in vitro and in vivo, and are associated with a lower level of plasma TNF-α. The peroxisome proliferator-activated receptor-gamma (PPARγ) also is involved in the anti-inflammatory effects of AT1R antagonists https://www.sciencedirect.com/science/article/pii/S002432052030655X

Angiotensin II reduces food intake by altering orexigenic (orexin) neuropeptide expression in the mouse hypothalamus​

Systemic Ang II (1 μg/kg · min) infusion in FVB mice rapidly reduced hypothalamic expression of neuropeptide Y (Npy) and orexin and decreased food intake at 6 h compared with sham-infused controls but did not change peripheral leptin, ghrelin, adiponectin, glucagon-like peptide, peptide YY, or cholecystokinin levels. These effects were completely blocked by the Ang II type I receptor antagonist candesartan or deletion of Ang II type 1a receptor. Thus, Ang II type 1a receptor-dependent Ang II signaling reduces food intake by suppressing the hypothalamic expression of Npy and orexin, likely via AMPK dephosphorylation. These findings have major implications for understanding mechanisms of cachexia in chronic disease states such as congestive heart failure and end-stage renal disease, in which the renin-angiotensin system is activated.
https://pubmed.ncbi.nlm.nih.gov/22234465/
 

Cipher

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On the topic of angiotensin II receptor blockers, here's a study finding positive effects from candesartan in patients with Alzheimer's disease:

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9683395/
 

pattismith

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Angiotensin II reduces food intake by altering orexigenic (orexin) neuropeptide expression in the mouse hypothalamus​

Systemic Ang II (1 μg/kg · min) infusion in FVB mice rapidly reduced hypothalamic expression of neuropeptide Y (Npy) and orexin and decreased food intake at 6 h compared with sham-infused controls but did not change peripheral leptin, ghrelin, adiponectin, glucagon-like peptide, peptide YY, or cholecystokinin levels.
That's interesting as orexin not only control appetite but also arousal.

I have high AT1R auto antibodies, and I think it may be the core pathway of my ME/CFS
 

datadragon

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I have high AT1R auto antibodies, and I think it may be the core pathway of my ME/CFS
While I found many different "roads" to orexin, yes hypothetically that can be one of them if it lowers orexin as it states. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. AT1R-AAs promoted inflammation through the expression of interleukin-6 (IL6), vascular cell adhesion molecule-1 (VCAM-1), and improved levels of NF-kB, a transcription factor that regulates many genes involved in inflammation. These effects were blocked by valsartan. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778295/ For YOU, taking a AT1R blocker it suggests might help.
 

datadragon

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I take that....started somewhat recently when my beta blocker was managing to control my high BP.......

Let us know how it helps you. It should be helpful either when AT1R is over activated or have autoantibodies that will also activate AT1R. That pathway is involved with IL-1β, IL-18, IFNγ, TNF-α, and IL-6 cytokine expression so perhaps those showing high c-reactive protein and inflammation may be helpful.
 

datadragon

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I'll leave this here since it shows the cytokine effects of different drugs on AT1R https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898045/

I just got tested for that and mine is "not high"......yet I feel so inflamed, go figure.

IFN-α which lowers orexin induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. Some show higher IL-10 levels (anti inflammatory). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350004/ So its looking like In that later state switching to sodium butyrate may help which restores TH1 as mentioned elsewhere rather than taking AT1R blockers which further reduce an inflammatory state to an anti inflammatory one and further upregulate IL-10.
 
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