adenylate cyclase br Introduction Increased renin angiotensi

Introduction Increased renin-angiotensin system (RAS) activity and inflammation in cardiovascular-related regions of the central nervous system contribute to the overactivity of neurohumoral systems that promote volume retention, cardiac remodeling and serious cardiac arrhythmias in systolic heart failure (HF). A primary central nervous system site involved in this process is the hypothalamic paraventricular nucleus (PVN), which contains both presympathetic and neuroendocrine neurons (Ferguson et al., 2008). Interventions that reduce RAS activity and inflammation in the PVN are uniformly successful in reducing sympathetic excitation and improving indices of volume regulation and cardiac hemodynamics in rats with HF (Zhang et al., 1999, Francis et al., 2001, Francis et al., 2004, Guggilam et al., 2008, Kang et al., 2008a, Kang et al., 2008b, Kang et al., 2010, Yu et al., 2012, Huang et al., 2014). However, the mechanisms upregulating the activity of these two excitatory neurochemical systems in the PVN in HF are still poorly understood. The present study sought to determine whether increased RAS activity in the subfornical organ (SFO) – a forebrain circumventricular organ that lacks an effective blood–brain barrier, senses circulating humoral factors in HF (McKinley et al., 2003, Ferguson, (2014)) and projects directly to the PVN (Li and Ferguson, 1993, Kawano and Masuko, 2010) – contributes to the inflammatory response in the PVN in HF. In HF, angiotensin II (AngII) type 1 receptors (AT1R) are upregulated in the SFO (Tan et al., 2004, Wei et al., 2008b), which is exposed to increased plasma levels of AngII in that setting (Huang and Leenen, 2009; Wang et al., 2014). Previous studies have shown that a slow-pressor infusion of AngII upregulates the adenylate cyclase of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and cyclooxygenase-2 (COX-2) in the PVN of normal rats (Yu et al., 2013b), and that chronic intracerebroventricular infusion of the AT1R blocker losartan significantly reduces the expression of the TNF-α, IL-1β and IL-6 in the PVN of HF rats (Kang et al., 2008a), though neither of those studies considered what role AT1R in the SFO might play in upregulating the expression of these neuroinflammatory mediators in the PVN. To address this question, we used an adeno-associated viral (AAV) vector carrying an shRNA specific for AT1aR, the AT1R subtype that mediates the effects of AngII in the SFO and other cardiovascular autonomic regions of the brain (Lenkei et al., 1997). We microinjected the AT1aR shRNA into the SFO prior to the induction of HF and measured the effects of AT1aR knockdown in the SFO on mRNA for TNF-α, IL-1β, COX-2 and markers of neuronal and glial activation in the SFO and PVN, on plasma AngII, TNF-α, norepinephrine (NE), arginine vasopressin (AVP), and on indices of cardiac remodeling and hemodynamics. The results reveal that activation of AT1aR in the SFO of HF rats promotes the expression of the inflammatory mediators in the PVN that contribute to neurohumoral excitation in HF.
Experimental procedures
Results
Discussion Previous studies have established that central neuroinflammation (Kang et al., 2008b; Yu et al., 2012, Yu et al., 2017), and in particular neuroinflammation in the PVN (Kang et al., 2009, Kang et al., 2010), plays an important role in the autonomic dysregulation of HF. Rats with HF following myocardial infarction have increased glial activation (Yu et al., 2010) and increased pro-inflammatory cytokine (PIC) levels in the PVN (Yu et al., 2010, Yu et al., 2012), and maneuvers that block or counter the actions of these inflammatory mediators in the PVN reduce sympathetic activity and improve cardiac hemodynamics (Kang et al., 2009, Yu et al., 2012). However, the mechanisms that upregulate inflammation in the PVN are still poorly understood.
Declarations of interests
Introduction