Angiotensin II Type 1a Receptors in the Subfornical Organ Modulate Neuroinflammation in the Hypothalamic Paraventricular Nucleus in Heart Failure Rats

Abstract

Inflammation in the hypothalamic paraventricular nucleus (PVN) contributes to neurohumoral excitation and its adverse consequences in systolic heart failure (HF). The stimuli that trigger inflammation in the PVN in HF are not well understood. Angiotensin II (AngII) has pro-inflammatory effects, and circulating levels of AngII increase in HF. The subfornical organ (SFO), a circumventricular structure that lacks an effective blood-brain barrier and senses circulating AngII, contains PVN-projecting neurons. We hypothesized that activation of AngII type 1a receptors (ATR) in the SFO induces neuroinflammation downstream in the PVN. Male rats received SFO microinjections of an adeno-associated virus carrying shRNA for ATR, a scrambled shRNA, or vehicle. One week later, some rats were euthanized to confirm the transfection potential and knockdown efficiency of the shRNA. Others underwent coronary artery ligation to induce HF or a sham coronary artery ligation (Sham). Four weeks later, HF rats that received the scrambled shRNA had increased mRNA in SFO and PVN for ATR, inflammatory mediators and indicators of neuronal and glial activation, increased plasma levels of AngII, tumor necrosis factor-α, norepinephrine and arginine vasopressin, and impaired cardiac function, compared with Sham rats that received scrambled shRNA. The central abnormalities were ameliorated in HF rats that received ATR shRNA, as were plasma norepinephrine and vasopressin. Sham rats that received ATR shRNA had reduced SFO ATR mRNA but no other changes compared with Sham rats that received scrambled shRNA. The results suggest that activation of ATR in the SFO upregulates the neuroinflammation in the PVN that contributes to neurohumoral excitation in HF.

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

“…These changes were accompanied by a reduction in the total number of activated (pro-in ammatory) microglia as well as reduced mRNA levels for IL-1β, IL-6 and TNF-α (61). Taken together, these previous studies pinpoint neuroin ammation, particularly microglial cell activation within the PVN, as a key underlying pathophysiological mechanism contributing to the sympathohumoral and cardiovascular complications associated with HF (23)(24)(25)(26). Given that the PVN is a key regulatory structure involved in the integration of behavioral, cardiovascular and neuroendocrine homeostatic responses (64)(65)(66), and is richly interconnected with a plethora of brain regions (32,(67)(68)(69), including the amygdala, it is reasonable to speculate that neuroin ammation could also contribute to mood and anxiety disorders associated to HF.…”

“…Lastly, it is important to note that while we report here signi cant changes in glial morphology and cytokine levels, it remains unclear whether these changes translate into altered glial function and how they might ultimately affect the pro-in ammatory state within the respective brain regions. Finally, most published studies in the eld using the congestive HF rodent model, including the present one, were performed in young adult rats (6-10 weeks), (23,26,(100)(101)(102). This is a caveat that needs to be taken into consideration, given that the incidence of HF in humans is higher in the elderly population.…”

“…Importantly, neuroin ammation within the PVN has been described as a hallmark pathophysiological mechanism contributing to increased sympathetic out ow during this disease (23)(24)(25)(26). The PVN is also recognized as an important center in emotional regulation and harbors a variety of cells producing different neuropeptides (27)(28)(29).…”

“…Moreover, a recent study highlighted the pivotal role of oxytocin signaling in the CeA in mouse models of depression (39). While neuroin ammation in the PVN of HF rats has been previously described (25,26), it is at present unknown whether HF-induced neuroin ammation in other brain areas, such as the CeA also occurs, and if so, how it temporally relates to the onset of neuroin ammation in the PVN.…”

Neuroinflammation in heart failure: new insights for an old disease

“…In fact, SFO is a major source for de novo synthesis of Ang‐II within the brain (Sinnayah et al . ) and it has been shown that AT1 knockdown in this nucleus in HFrEF rats reduces the expression of TNF‐α, IL‐1β, CD68 (a marker of microglial activation) and c‐Fos (a marker of neuronal activation) in the PVN, diminishes plasma NA, and slightly restored cardiac function, without affecting plasma cytokines or Ang‐II (Yu, ). However, the contribution of SFO in HFpEF pathophysiology is completely unknown (Table ), despite evidence strongly suggesting that it could play a major role in HFpEF pathophysiology.…”