Augmented Upregulation by c- fos of Angiotensin Subtype 1 Receptor in Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats

Abstract

Abstract-Our laboratory demonstrated previously that spontaneously hypertensive rats (SHR) exhibited an elevated basal Fos expression in the nucleus tractus solitarii (NTS), the terminal site for primary baroreceptor afferents, and that Fos protein is required for the re-expression of angiotensin subtype 1 receptor (AT1R) mRNA in the NTS after baroreceptor activation. The present study evaluated the hypothesis that this re-expression of AT1R is augmented in SHR and is promoted by the heightened Fos expression. Reverse transcription-polymerase chain reaction analysis revealed that baroreceptor activation via sustained increase in systemic arterial pressure resulted in a discernible reduction in the expression of AT1R mRNA at the dorsomedial medulla of SHR and normotensive Wistar-Kyoto rats. However, SHR manifested an appreciably larger magnitude of decline, followed by a faster time course of re-expression in AT1R mRNA. Parallel findings were obtained from the pressor response induced by microinjection unilaterally of angiotensin II (40 pmol) into the NTS. Whereas the re-expression of AT1R at both transcriptional and functional expression levels after baroreceptor activation was discernibly blunted by prior bilateral application into the NTS of an antisense c-fos oligonucleotide (50 pmol), the suppression in SHR was again significantly more intense. Control pretreatment with the corresponding sense or scrambled c-fos oligonucleotide was ineffective. We conclude that the heightened Fos expression in SHR is causatively related to the augmented re-expression of AT1R in the NTS at both transcriptional and functional levels.

Role of Oxidant Stress on AT1 Receptor Expression in Neurons of Rabbits With Heart Failure and in Cultured Neurons

“…39 Chan et al showed an augmented upregulation by c-fos of AT1R in the NTS of spontaneously hypertensive rats. 40 Fleegal et al demonstrated that Ang II induction of AP-1 in neurons requires stimulation of Jnk. 41 We previously showed that phosphorylated c-Jun and c-Jun mRNA increased in the RVLM of CHF rabbits.…”

Nitric Oxide Regulates c-fos Expression in Nucleus Tractus Solitarii Induced by Baroreceptor Activation via cGMP-Dependent Protein Kinase and cAMP Response Element-Binding Protein Phosphorylation

“…Furthermore, Fos expression in the NTS represents an early intracellular event that leads to long-term inhibitory modulation of BRR response (Shih et al, 1996;Chan et al, 1997). Moreover, a heightened Fos expression is associated with reduced BRR response in spontaneously hypertensive rats (Chan et al, 1998a(Chan et al, , 2002. Intriguingly, this heightened Fos expression is causally related to the augmented expression of angiotensin subtype 1 receptor in the NTS of spontaneously hypertensive rats after baroreceptor activation (Chan et al, 2002).…”

“…Moreover, a heightened Fos expression is associated with reduced BRR response in spontaneously hypertensive rats (Chan et al, 1998a(Chan et al, , 2002. Intriguingly, this heightened Fos expression is causally related to the augmented expression of angiotensin subtype 1 receptor in the NTS of spontaneously hypertensive rats after baroreceptor activation (Chan et al, 2002). As such, it is the interplay rather than relative importance of NO, c-fos, and angiotensin receptors in the NTS that is crucial to BRR control of circulation.…”

Novel Mechanisms of Sympathetic Regulation in Chronic Heart Failure

“…55 Activation of specific transcription factors that mediate upregulation of the AT 1 receptor message and protein may also be operative through the c-Jun/JNK/c-fos pathway. 56 It is worth noting that chronically high levels of Ang II regulate membrane potential by altering the expression of potassium channel proteins and potassium currents. [57][58][59] This mechanism may be very important in the setting of various disease states that are characterized by sympathoexcitation, such as CHF and hypertension.…”