Angiotensin II-mediated neuroinflammation in the hippocampus contributes to neuronal deficits and cognitive impairment in heart failure rats
| Autor: | Elba Campos-Lira, Ferdinand Althammer, Ranjan Roy, Matthew Kirchner, Kathryn Whitley, Steve Davis, Juliana Montanez, Hildebrando Ferreira-Neto, Usama Zafar, Marise Parent, Javier Stern |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Physiology. 38 |
| ISSN: | 1548-9221 1548-9213 |
| Popis: | Background: Chronic hypertension can lead to the development of heart failure (HF), a debilitating disease affecting ~65 million people worldwide. In addition to impaired cardiovascular performance and associated systemic complications, most patients with HF suffer from depression and/or cognitive decline. Although neuroinflammation and brain hypoperfusion occur in humans and rodents with heart failure (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 humans, 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 angiotensin II AT1a receptors (AngII-AT1aRs) in hippocampal microglia preceded the onset of neuroinflammation. Importantly, blockade of AT1Rs with a clinically used therapeutic drug (losartan) efficiently reversed neuroinflammatory endpoints (but not hypoperfusion/hypoxia ones), resulting in turn in improved cognitive performance in HF rats. Finally, we show than circulating AngII leaks and access the hippocampal parenchyma in HF rats, constituting a likely source initiating the neuroinflammatory cascade. Conclusions: We provide compelling evidence for a novel mechanism that contributes to cognitive deficits in HF. We identified a neuronal substrate (hippocampus), a novel mechanism (Angiotensin II-driven neuroinflammation) and a potential novel neuroprotective therapeutic target (AngII-AT1aRs) for the treatment of cognitive deficits in HF. DFG Postdoc Fellowship AL 2466/1-1 to FA; National Heart, Lung, and Blood Institute Grant NIH HL090948 to JES, National Institute of Neurological Disorders and Stroke Grant NIH NS094640 to JES and funding provided by the Center for Neuroinflammation and Cardiometabolic Diseases (CNCD) at Georgia State University. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process. |
| Databáze: | OpenAIRE |
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