Angiotensin II Type 1a Receptor Knockdown in Subfornical Organ Attenuates Central Expression of Inflammatory Mediators and Ameliorates Peripheral Manifestations of Heart Failure in Rats After Myocardial Infarction
Authors: Yu Yang , Wei Shun‐Guang , Weiss Robert M , Felder Robert B 
Published: November 2023

Myocardial infarction (MI)‐induced heart failure (HF) is characterized by increased proinflammatory cytokines (PICs) and renin‐angiotensin system (RAS) activity in the periphery and in the brain, contributing to sympathetic excitation and the progression of HF. Although circulating angiotensin II (ANGII) and PICs can both up‐regulate inflammation and RAS activity in cardiovascular regions of the brain, their interactions within the brain in HF remains unclear. Receptors for ANGII and PICs are highly expressed in the subfornical organ (SFO), a forebrain circumventricular organ that lacks a blood–brain barrier and senses circulating humoral factors. We previously reported (FASEB J., 30:1b719, 2016) that knockdown of the tumor necrosis factor‐α (TNF‐α) receptor 1 (TNFR1) in the SFO of HF rats reduced the expression of RAS and inflammatory components in the SFO and downstream in the hypothalamic paraventricular nucleus (PVN), with improvements in indices of sympathetic drive and hemodynamic function. The present study examined the effect of knocking down the ANGII type 1a receptor (AT1aR) in the SFO of HF rats. Rats received SFO microinjections of an adeno‐associated viral vector carrying AT1aR shRNA or a scrambled shRNA and green fluorescent protein (GFP). One week later, transfection potential and knockdown efficiency were examined in some rats receiving shRNAs; other rats underwent coronary ligation to induce HF confirmed by echocardiography, or a sham operation. One week after SFO microinjections of AT1aR shRNA or scrambled shRNA, GFP fluorescence was visualized in the SFO but not in other brain areas. Rats receiving AT1aR shRNA also had significantly reduced AT1aR mRNA in the SFO compared with rats receiving scrambled shRNA. Four weeks after MI, HF+scrambled shRNA rats had increased mRNA for AT1aR, TNF‐α, TNFR1, interleukin (IL)‐1β, cyclooxygenase (COX)‐2, c‐fos (a marker of neuronal excitation), GFAP (an astrocyte marker) and CD68 (a microglial marker) in SFO and in PVN, along with increased plasma norepinephrine levels and lung/body weight and right ventricle/body weight ratios, compared with SHAM+scrambled shRNA rats. All of these abnormalities were ameliorated in the HF+AT1aR shRNA rats, that had reduced mRNA for AT1aR. Notably, SHAM+AT1aR shRNA rats also had reduced AT1aR mRNA in the SFO, but did not exhibit alterations in expression of the above mediators in the SFO and PVN, compared with SHAM+ scrambled shRNA rats. The results support the view that circulating ANGII, acting upon AT1aR in the SFO, upregulates the inflammatory response in the SFO with downstream effects in the PVN. Taken together with our previous study of the effects of TNFR1 knockdown in SFO, these results suggest that the SFO is a site at which reciprocal facilitatory interactions occur between RAS and PICs, both contributing to sympathetic excitation in HF, and that interrupting either may have beneficial effects. Astrocytes or microglia that express receptors for both ANGII and PICs may play a role in mediating these interactions.

Support or Funding Information

Supported by NIH RO1 HL‐073986 and Department of Veterans Affairs.