Systemic Sympathoexcitation Was Associated with Paraventricular Hypothalamic Phosphorylation of Synaptic CaMKIIα and MAPK/ErK

Abstract

Systemic administration of adrenergic agonist (Isoproterenol; ISOP) is known to facilitate cardiovascular changes associated with heart failure through an upregulation of cardiac toll-like receptor 4 (TLR4). Furthermore, previous studies have shown that cardiac tissue-specific deletion of TLR4 protects the heart against such damage. Since the autonomic regulation of systemic cardiovascular function originates from pre-autonomic sympathetic centers in the brain, it is unclear how a systemically driven sympathetic change may affect the pre-autonomic paraventricular hypothalamic nuclei (PVN) TLR4 expression. Here, we examined how change in PVN TLR4 was associated with alterations in the neurochemical cytoarchitecture of the PVN in systemic adrenergic activation. After 48 h of intraperitoneal 150 mg/kg ISOP treatment, there was a change in PVN CaMKIIα and MAPK/ErK expression, and an increase in TLR4 in expression. This was seen as an increase in p-MAPK/ErK, and a decrease in synaptic CaMKIIα expression in the PVN (p < 0.01) of ISOP treated mice. Furthermore, there was an upregulation of vesicular glutamate transporter (VGLUT 2; p < 0.01) and a decreased expression of GABA in the PVN of Isoproterenol (ISOP) treated WT mice (p < 0.01). However, after a PVN-specific knockdown of TLR4, the effect of systemic administration of ISOP was attenuated, as indicated by a decrease in p-MAPK/ErK (p < 0.01) and upregulation of CaMKIIα (p < 0.05). Additionally, loss of inhibitory function was averted while VGLUT2 expression decreased when compared with the ISOP treated wild type mice and the control. Taken together, the outcome of this study showed that systemic adrenergic activation may alter the expression, and phosphorylation of preautonomic MAPK/ErK and CaMKIIα downstream of TLR4. As such, by outlining the roles of these kinases in synaptic function, we have identified the significance of neural TLR4 in the progression, and attenuation of synaptic changes in the pre-autonomic sympathetic centers.

Revisiting the physiological effects of exercise training on autonomic regulation and chemoreflex control in heart failure: does ejection fraction matter?

“…Besides the RVLM, other brain regions have been also described as potential contributors to sympathoexcitation in HF (8,78,119). Indeed, the nucleus of the tractus solitarius (NTS), which represents the primary central integration site for peripheral chemoreceptor and baroreceptor activity, has been identified as a master regulator of chemoreflex and baroreflex function (36).…”

Exercise Training Attenuates Hypertension via Suppressing ROS/MAPK/NF-κB/AT-1R Pathway in the Hypothalamic Paraventricular Nucleus

“…MAPK, including p44/42 MAPK, JNK, and p38 MAPK as the major family members, plays pivotal roles in heart failure [ 53 ] and hypertension [ 54 ]. Recently, it was reported that phosphorylation of the MAPK within the PVN contributes to excessive RSNA, and the p44/42 MAPK inhibitor, PD-98059, micro-injected in the PVN significantly reduces RSNA in both heart failure [ 26 ] and ANG II-induced hypertensive rats [ 54 ].…”

Intermedin in Paraventricular Nucleus Attenuates Ang II-Induced Sympathoexcitation through the Inhibition of NADPH Oxidase-Dependent ROS Generation in Obese Rats with Hypertension

“…MAPK/ERK was more highly expressed in the PVN of SHR by the fourth week [36]. Ang II-mediated activation of MAPK/ERK increased vesicular release of presynaptic glutamate in the brain [37].…”

“…Thus, Ang II-induced sympathoexcitation in the PVN, may involve the alteration of excitatory (glutamate and cathecolamines) and inhibitory (GABA) neurotransmitter systems through ROS-ERK signaling pathways [38]. Recent studies demonstrated that ERK signaling in PVN can modulate SNA to affect cardiovascular function [36,39]. For instance, the anti-obesity effect of nesfatin-1 is mediated by hypothalamic ERK-dependent sympathoexcitation in obese animals [39].…”