Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8840722 | Neuroscience | 2018 | 13 Pages |
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 (AT1aR) in the SFO induces neuroinflammation downstream in the PVN. Male rats received SFO microinjections of an adeno-associated virus carrying shRNA for AT1aR, 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 AT1aR, 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 AT1aR shRNA, as were plasma norepinephrine and vasopressin. Sham rats that received AT1aR shRNA had reduced SFO AT1aR mRNA but no other changes compared with Sham rats that received scrambled shRNA. The results suggest that activation of AT1aR in the SFO upregulates the neuroinflammation in the PVN that contributes to neurohumoral excitation in HF.
Keywords
AT1RCOX-2PICCOX-1PGE2IL-1βTNFR1AAVAVPSFOANGIILVEFCD68LVEDVLVEDPAT1ARleft ventricular peak systolic pressureACENF-κBLPSIL-6GFAPDBPGFPdP/dtmaxangiotensin converting enzymeAngiotensin IIinterleukin-6Interleukin-1 betaconleft ventricleleft ventricular end diastolic volumeCluster of differentiation 68Proinflammatory cytokinecyclooxygenase-1Cyclooxygenase-2Heart rateSubfornical organTNF-αnuclear factor κBdiastolic blood pressureleft ventricular end diastolic pressurelipopolysaccharidePVNSystolic heart failurenorepinephrineHypothalamic paraventricular nucleusarginine vasopressinbody weightAdeno-associated virusGlial fibrillary acidic proteingreen fluorescent proteinProstaglandin E2left ventricular ejection fractionControl
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Authors
Yang Yu, Shun-Guang Wei, Robert M. Weiss, Robert B. Felder,