ERK1/2 as a molecular switch for the initiation of long-term pressor response to central angiotensin II

Accumulating evidence indicates that octapeptide angiotensin II plays a key role in central cardiovascular control, and hyperactivity of the brain angiotensin II system contributes to neurogenic hypertension [1–3]. The precise cellular and molecular mechanisms underlying hyperactivity of the brain angiotensin II system in hypertension have not been fully elucidated. Previous studies have suggested that both an increase in brain angiotensin II levels and angiotensin II type 1 (AT1) receptor upregulation could play a role [4–6]. Considerable in-vitro evidence also indicates that alterations in AT1 receptor signaling pathways that employ mitogen-activated protein kinases (MAPK), and especially extracellular signal-regulated protein kinase 1/2 (ERK1/2), could be important [3,7]. In particular, it has been shown that the neuronal AT1 receptor is coupled to the ERK1/2 signaling pathway and that this pathway modulates, via stimulation of activator protein 1 (AP-1) transcription factors c-Fos and c-Jun, long-term modulatory effects of angiotensin II on neuronal activity and excitability [8–11]. The role of the AT1 receptor–ERK1/2–c-fos pathway in mediating prohypertensive effects of central angiotensin II in vivo has not been yet investigated. This issue of the Journal of Hypertension presents an article by Chan and colleagues [12], who show that the long-term intracerebroventricular infusion of angiotensin II in rats increases blood pressure and AT1 receptor expression in the rostral ventrolateral medulla (RVLM) via the protein kinase C (PKC)–ERK1/2–c-fos pathway. This finding suggests a potential molecular mechanism by which brain AT1 receptors could be upregulated by angiotensin II, leading to a chronic hyperangiotensinergic state, and possibly hypertension. This finding is consistent with earlier observations that the continuous or repetitive administration of angiotensin II into rat brain ventricles produces a substantial increase in AT1 receptor expression [5,13,14], along with activation of several transcription factors, including c-Fos and c-Jun [14]. It thus appears that angiotensin II, acting through the induction of immediate early genes, can upregulate RVLM AT1 receptors to provide a positive feedback loop for the potentiation of its central sympathoexcitatory effects. This amplification mechanism seems not to be limited to the brain, as previous evidence suggests a direct correlation between the pressure overload-induced increase in angiotensin II levels and the AP-1-dependent transcription of the AT1 receptor gene in cardiac myocytes resulting in the potentiation of angiotensin II effects [15]. Although in the study by Chan et al.[12] sustained 24-h inhibition of the ERK1/2 pathway in the RVLM attenuated angiotensin II-induced hypertension, blood pressure remained unaltered in control normotensive animals. These results indicate that activation of the ERK1/2 pathway may be specifically linked to a hyperangiotensinergic state in the brain. It is thus possible that ERK1/2 may represent a potential target for the treatment of some forms of angiotensin II-dependent neurogenic hypertension. Conversely, inhibition of the ERK1/2 pathway by PD98059 in the RVLM induced a substantial decrease in blood pressure in both normotensive and spontaneously hypertensive rats [16], indicating that, under experimental conditions, ERK1/2 modulated the tonic activity of RVLM vasomotor neurons. The reasons for this disparity are not entirely clear, and therefore further studies are necessary before conclusions can be drawn regarding the role of RVLM ERK1/2 in the tonic regulation of blood pressure. An intriguing finding of Chan et al.[12] is that p38 MAPK plays little role in the RVLM in mediating the long-term pressor effect of angiotensin II. Conversely, the same group has recently shown that p38 MAPK mediated the acute pressor effect of angiotensin II via enhancement of glutamate release in the RVLM, whereas ERK1/2 was not essential in this effect of the octapeptide [17]. Taken together, these observations pinpoint a unique molecular switch that activates distinct signaling pathways mediating the acute and chronic pressor effects of central angiotensin II. Little effect of ERK1/2 inhibition on the acute pressor action of angiotensin II in the RVLM [17] may seem to contradict previous findings that ERK1/2 in the RVLM is necessary for the full expression of the acute pressor response to local angiotensin II in normotensive and spontaneously hypertensive rats [16]. Although the reasons for the disparity are not clear, it is of note that in the earlier study [16], the pressor response to angiotensin II was tested during the later phase (7–14 h) of ERK1/2 inhibition in the RVLM. It is thus possible that by this time sustained inhibition of ERK1/2 could result in changes in AT1 receptor expression [12] or potassium channel function [18]. These changes might in turn affect the excitability of RVLM presympathetic neurons and thereby the pressor response to the acute administration of angiotensin II. It is thus conceivable that, although ERK1/2 is not directly involved in mediating the acute pressor response to angiotensin II, it may still indirectly influence this response. Another novel finding of Chan et al.[12] is that the β isoform of PKC, but not the α or γ isoforms of this kinase, plays a role in the activation of the ERK1/2–c-fos cascade in response to the long-term infusion of angiotensin II. These calcium-dependent PKC isozymes have been implicated so far in the acute chronotropic actions of angiotensin II on brainstem and hypothalamic neurons [7,19]. Interestingly, it has been shown that PKC antisense oligonucleotides against the α, but not β or γ isoforms of PKC abolished the acute inhibitory effect of angiotensin II on neuronal potassium current, suggesting that an angiotensin II-mediated increase in the neuronal firing rate involves the activation of PKCα [20]. Collectively, these data imply that the α and β isoforms of PKC can act as another molecular switch between the acute, short-term actions of angiotensin II on neuronal activity via changes in membrane ionic currents and its long-term actions via regulation of gene expression and protein synthesis. In conclusion, the article by Chan and colleagues [12] provides important evidence for the selective involvement of the PKCβ–ERK1/2–c-fos signaling pathway in the RVLM in the blood pressure increase caused by the long-term infusion of angiotensin II into brain ventricles. Taken together with a recent report from the same group that local p38 MAPK, but not ERK1/2, is essential in the acute pressor effect of angiotensin II [17], the present study suggests that p38 MAPK and ERK1/2 form a molecular switch that triggers acute and chronic pressor responses to angiotensin II. Importantly, angiotensin II-induced activation of the PKCβ–ERK1/2–c-fos pathway and the resulting AT1 receptor upregulation may provide a potential mechanism for the development of a chronic hyperangiotensinergic state leading to sympathetic hyperactivity and hypertension. The physiological and pathological mechanisms that may cause the activation of the brain angiotensin II system are not fully understood, and may include both genetic and environmental components. Given the role of angiotensin II as a stress mediator in the brain [21–23], and specifically in the RVLM [24], it is tempting to suggest that recurrent exposure to stress may substantially increase brain angiotensin II levels, which in turn may lead to the ERK1/2–c-fos-dependent overexpression of AT1 receptors resulting in the potentiation of angiotensin II effects. Further studies are clearly necessary, however, to determine whether AT1 receptor–ERK1/2–c-fos signaling, in cardiovascular-relevant brain areas, plays a role in the pathogenesis of neurogenic hypertension and related cardiovascular disorders.