The paraventricular nucleus and heart failure

Abstract

New Findings r What is the topic of this review?This review gives an update on the cellular and molecular mechanisms within the autonomic nervous system involved in non-pathological and pathological cardiovascular regulation. r What advances does it highlight?For cardiovascular homeostasis in non-pathological conditions to be maintained, discrete neural networks using specified signalling mechanisms at both cellular and molecular levels are required. In heart failure, the cell signalling protein partners CAPON and PIN decrease the bioavailability of nitric oxide by inhibiting neuronal nitric oxide synthase activity, leading to the removal of tonic neuronal inhibition. Following a myocardial infarction, pro-inflammatory cytokines in the paraventricular nucleus and the subsequent generation of reactive oxygen species, via angiotensin II activation of the angiotensin II type 1 receptor, increase neuronal excitability further, leading to sympathetic excitation.A pathological feature of heart failure is abnormal control of the sympathetic nervous system. The paraventricular nucleus of the hypothalamus (PVN) is one of the most important central sites involved in regulating sympathetic tone and is, in part, responsible for the dysregulation of the sympathetic nervous system evident in heart failure. Generation of sympathetic tone in response to fluctuations in cardiovascular regulation uses discrete anatomical pathways and neurochemical modulators. Direct and indirect projections from the PVN pre-autonomic neurons innervate the sympathetic preganglionic neurons in the spinal cord, which in turn innervate sympathetic ganglia that give rise to the sympathetic nerves. Pre-autonomic neurons of the PVN themselves receive an afferent input arising from the nucleus tractus solitarii, and viscerosensory receptors convey cardiovascular fluctuations to the nucleus tractus solitarii. The PVN contains excitatory and inhibitory neurons, whose balance determines the sympathetic tone. In non-pathological conditions, the tonic inhibition of the PVN pre-autonomic neurons is mediated by GABA-and NO-releasing neurons. In heart failure, the pre-autonomic neurons are disinhibited by the actions of the excitatory neurotransmitters glutamate and angiotensin II, leading to increased sympathetic activity. A key feature of the disinhibition is a reduction in the bioavailability of NO as a consequence of disrupted CAPON and PIN signalling mechanisms within the neuron. Another critical feature that contributes to increased neuronal excitation within the PVN is the production of pro-inflammatory cytokines immediately following a myocardial infarction, the activation of the angiotensin II type 1 receptor and the production of reactive oxygen species. By examining the changes associated with the sympathetic nervous system pathway, we will progress our understanding of sympathetic regulation in heart failure, identify gaps in our knowledge and suggest new therapeutic strategies.

Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus

“…For example, ANG II-mediated ROS production within the PVN contributes to cardiovascular diseases with high sympathetic drive, such as hypertension and heart failure (9,43,59,74). However, the cellular sources and molecular targets involved in ANG II-ROS signaling dysregulation have not been fully elucidated.…”

Corticolimbic regulation of cardiovascular responses to stress

“…The LHA inhibits tachycardic responses to stress via the parasympathetic nervous system [98], while the mPOA mediates stress effects of angiotensin on mean arterial pressure (MAP) and vascular resistance [99]. The PVH has multiple mechanisms for bi-directional control of HR and blood pressure responses [100,101], although net synaptic activity in the PVH facilitates cardiovascular stress responses [102]. The NTS is an integral component of autonomic integration and possesses great neurochemical diversity [91,103,104].…”

Vagal afferents, sympathetic efferents and the role of the PVN in heart failure

“…In HF the preautonomic neurons 78 become disinhibited leading to increased sympathetic activity. The fundamental 79 mechanism underpinning sympatho-excitation in HF involves loss of NOS signalling 80 Again, the role neurotransmitters play in abnormal sympatho-excitaion in HF has 84 been extensively reviewed (Pyner, 2009(Pyner, , 2014. To focus on NO, within the brain, all 85 three isoforms of NOS, inducible (iNOS), endothelial (eNOS) and neuronal (nNOS) 86 contribute to the production of NO (Stern, 2004).…”