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.
Highlights
Paraventricular hypothalamic adrenergic neurotransmission forms part of the pre-autonomic control of systemic cardiovascular function (Xu et al, 2012; Lee et al, 2013; Patel et al, 2016)
After βARA, in confocal microscopy, we found a significant decrease in total MAPK/ErK expression within the paraventricular hypothalamic nuclei (PVN) of the WT/ISOP group when compared with the control (Figures 2a,b; p < 0.05)
Alterations in MAPK/ErK and p-MAPK/ErK were accompanied by a significant loss of CaMKIIα in the PVN neurons of ISOP treated mice when compared with the control (Figures 2d,e)
Summary
Paraventricular hypothalamic adrenergic neurotransmission forms part of the pre-autonomic control of systemic cardiovascular function (Xu et al, 2012; Lee et al, 2013; Patel et al, 2016). In the presence of a βAR agonist, such as isoproterenol (ISOP), G-protein is released leading to the activation of PIP3 which initiate cascades of signaling events involving the phosphorylation of downstream kinases (Dawaliby et al, 2016; Ranjan et al, 2016). In support of this proposition, the transcription of Ras/Raf/MAPK genes increases after ISOP treatment and is associated with TLR4 signaling (Kim et al, 2006; Lu et al, 2014; Theccanat et al, 2016). A cardiac tissue-specific deletion of TLR4 prevents cardiac tissue damage after ISOP treatment (Kim et al, 2006)
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