Published online before print September 2, 2008, doi: 10.1161/HYPERTENSIONAHA.108.113639
(Hypertension. 2008;52:679.)
© 2008 American Heart Association, Inc.
Original Articles |
Mitogen-Activated Protein Kinases Mediate Upregulation of Hypothalamic Angiotensin II Type 1 Receptors in Heart Failure Rats
From the Department of Internal Medicine (S.-G.W., Y.Y., Z.-H.Z., R.M.W., R.B.F.), Neuroscience Program (S.-G.W., R.B.F.), University of Iowa Carver College of Medicine and Veterans Affairs Medical Center (R.M.W., R.B.F.), Iowa City.
Correspondence to Robert B. Felder, MD, University of Iowa College of Medicine, E318-GH, 200 Hawkins Dr, Iowa City, IA 52242. E-mail robert-felder{at}uiowa.edu
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Abstract |
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In heart failure (HF), angiotensin II type 1 receptor (AT1-R) expression is upregulated in brain regions regulating sympathetic drive, blood pressure, and body fluid homeostasis. However, the mechanism by which brain AT1-R are upregulated in HF remains unknown. The present study examined the hypothesis that the angiotensin II (Ang II)–triggered mitogen-activated protein kinases (MAPKs) p44/42, p38, and c-Jun N-terminal kinase contribute to upregulation of the AT1-R in the hypothalamus of rats with HF. AT1-R protein, AT1-R mRNA, and AT1-R immunoreactivity increased in the paraventricular nucleus of hypothalamus and the subfornical organ of rats with ischemia-induced HF compared with sham-operated controls. Phosphorylated p44/42 MAPK, c-Jun N-terminal kinase, and p38 MAPK also increased in paraventricular nucleus and subfornical organ. A 4-week ICV infusion of the AT1-R antagonist losartan decreased AT1-R protein and phosphorylation of p44/42 MAPK, c-Jun N-terminal kinase, and p38 MAPK in the HF rats. A 4-week ICV infusion of the p44/42 MAPK inhibitor PD98059 or the c-Jun N-terminal kinase inhibitor SP600125 significantly decreased AT1-R protein and AT1-R immunoreactivity in the paraventricular nucleus and subfornical organ, but the p38 MAPK inhibitor SB203580 did not. Treatment with ICV losartan, PD98059, and SP600125 had no effect on AT1-R expression by Western blot in sham-operated rats. In untreated HF rats 4 weeks after coronary ligation, a 3-hour ICV infusion of PD98059, SP600125, or losartan reduced AT1-R mRNA in paraventricular nucleus and subfornical organ. These data indicate that MAPK plays an important role in the upregulation of AT1-R in the rat forebrain in HF and suggest that Ang II upregulates its own receptor by this mechanism.
Key Words: MAPK • Ang II • AT1 receptor • heart failure • forebrain
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Introduction |
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The intrinsic brain renin-angiotensin system (RAS) is activated in heart failure (HF).1,2 Increased activity of the brain RAS is thought to play a pivotal role in the progression of HF by altering salt and water homeostasis, neurohormonal release, and sympathetic outflow.3,4 The fundamental functions of brain RAS are mediated by angiotensin II (Ang II), acting on the angiotensin II type 1 receptor (AT1-R), which is widely distributed in the central nervous system from the forebrain to the brain stem.5
In HF, AT1-R expression is upregulated in the subfornical organ (SFO) and the organum vasculosum of the laminae terminalis, circumventricular organs lacking a blood–brain barrier, and in discrete nuclei inside the blood–brain barrier, including the paraventricular nucleus (PVN), the median preoptic nucleus, the nucleus tractus solitarius, and the rostral ventrolateral medulla.6,7 These are the key brain regions regulating blood pressure, body fluid homeostasis, and sympathetic drive. The intracellular mechanisms by which brain AT1-R are upregulated in these regions in HF remain unknown.
Chronic ICV infusion of Ang II increases the expression of AT1-R in the brain of rats8,9 and rabbits.6 These findings, along with the increase in brain AT1-R in high renin states like hypertension and HF, suggest that Ang II may upregulate its own receptor. Ang II binding to the AT1-R robustly activates the mitogen-activated protein kinase (MAPK) intracellular signaling pathways.10 Three major MAPK family members are p44/42 MAPK (also known as extracellular signal-regulated protein kinase 1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK). p44/42 MAPK is responsible for the transcriptional regulation of c-Fos,11 whereas JNK is responsible for the phosphorylation of c-Jun.12 c-Fos and c-Jun are primary components of the nuclear transcription factor activator protein 1 (AP-1).13 In rats, peripheral or central administration of Ang II induces strong expression of c-Fos and c-Jun in several cardiovascular autonomic regions of the forebrain, including the SFO and the PVN.14,15 Furthermore, AP-1 binding sequences have been identified in the upstream promoter of the cloned AT1-R gene of the rat,16 suggesting that Ang II–induced MAPK signaling may lead to upregulation of the AT1-R.
We tested the hypothesis that Ang II upregulates AT1-R expression in the brain of HF rats by inducing MAPK activity. We examined the contribution of the MAPK signaling pathways to expression of AT1-R in 2 representative regions: the SFO, which lies outside the blood–brain barrier and is exposed to circulating Ang II synthesized by the systemic RAS, and the PVN, which is protected by the blood-brain barrier but is exposed to Ang II synthesized by the intrinsic brain RAS.
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Materials and Methods |
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Animals
Adult male Sprague-Dawley rats, weighing 275 to 300 g, were obtained from Harlan Sprague Dawley (Indianapolis). The animals were housed in temperature-controlled (23±2°C) rooms in the University of Iowa animal care facility and exposed to a normal 12-hour light/dark cycle. They were provided with rat chow ad libitum. These studies were performed in accordance with the Guiding Principles for Research Involving Animals and Human Beings of the American Physiological Society.17 The experimental procedures were approved by the University of Iowa Institutional Animal Care and Use Committee.
Experimental Protocols
Rats underwent coronary artery ligation to induce HF or a sham operation and were assigned to one of the following protocols.
Protocol I
Rats underwent a 4-week ICV infusion (0.25 µL/hour) of the AT1-R antagonist losartan (10 mmol/L), the p44/42 MAPK inhibitor PD98059 (20 µmol/L), the JNK inhibitor SP600125 (100 µmol/L), the p38 MAPK inhibitor SB203580 (100 µmol/L), or vehicle (VEH), beginning within 24 hours of coronary ligation or sham surgery. These rats were used for Western blot or immunohistochemistry studies measuring AT1-R and MAPK protein expression in PVN and SFO. In this protocol, rats in the immunohistochemistry study groups underwent echocardiography and assessment of the effects of chronic ICV infusions of losartan and the MAPK inhibitors on hemodynamic and anatomic indicators of HF.
Protocol II
Rats underwent a 3-hour ICV infusion (40 µL/hour) of losartan (10 mmol/L), PD98059 (20 µmol/L), SP600125 (100 µmol/L), SB203580 (100 µmol/L), or VEH 4 weeks after coronary artery ligation or sham surgery. These rats were used for real-time polymerase chain reaction studies measuring the contribution of MAPK to AT1-R mRNA expression in PVN and SFO. All rats in this protocol underwent echocardiography and assessment of the effects of acute ICV infusions of losartan and the MAPK inhibitors on hemodynamic and anatomic indicators of HF.
Specific Materials and Methods
Specific materials and methods are available in the online data supplement (http://hyper.ahajournals.org).
Statistics
All values are expressed as the means±SEM. The significance of differences among groups was analyzed by 2-way repeated-measure ANOVA followed by post hoc Fisher’s least significant difference test. Echocardiographic parameters were analyzed using 1-way ANOVA followed by Fisher’s least significant difference test. Differences between values were considered significant at P<0.05.
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Results |
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Protocol I: Chronic ICV infusion of Losartan and MAPK Inhibitors
Molecular Studies
Western blot revealed significant increases in phosphorylated p44/42 MAPK (p-p44/42), phosphorylated JNK (p-JNK), and phosphorylated p38 MAPK (p-p38) in PVN (Figure 1A) and SFO (Figure 1B) of VEH-treated HF rats compared with VEH-treated sham-operated rats. ICV infusion of losartan for 4 weeks markedly reduced the level of p-p44/42, p-JNK, and p-p38 in PVN (Figure 1A) and SFO (Figure 1B) in HF rats but had no effects on these variables in sham-operated rats.
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P<0.05 HF+Losartan compared with HF+VEH. Representative Western bands are shown above each bar.AT1-R protein was also significantly increased in PVN (Figure 2A) and SFO (Figure 2B) of VEH-treated HF versus VEH-treated sham-operated rats. HF rats treated for 4 weeks with ICV losartan had a substantially lower level of AT1-R protein in the PVN and SFO than VEH-treated HF rats (Figure 2). HF rats treated ICV for 4 weeks with the p44/42 MAPK inhibitors PD98059 or the JNK inhibitor SP600125 also had lower AT1-R protein levels in PVN (Figure 2A) and SFO (Figure 2B) compared with VEH-treated HF rats. ICV treatment for 4 weeks with SB203580, a p38 MAPK inhibitor, had no effect on AT1-R protein levels (Figure 2). In sham-operated rats, ICV infusion of losartan, PD98059, and SP600125 for 4 weeks had no effect on AT1-R expression in the PVN or the SFO (Figure 2).
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Immunohistochemical Studies
Immunoreactivity for p-p44/42, p-p38, and p-JNK was increased in PVN (Figure 3) and SFO (Figure 4) in VEH-treated HF rats compared with VEH-treated sham-operated rats. The number of neurons containing phosphorylated MAPK in dorsal parvocellular (PVN-dp), medial parvocellular (PVN-mp), ventrolateral parvocellular (PVN-vlp), and posterior magnocellular (PVN-pm) subdivisions of the PVN18 (Figure 3) as well as in central SFO (Figure 4) was significantly higher in VEH-treated HF rats than in VEH-treated sham-operated rats.
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Immunoreactivity for AT1-R, identified with a rabbit polyclonal AT1-R antibody (ab18801; Abcam, Inc; Cambridge, MA), was also increased in all 4 regions (PVN-dp, PVN-mp, PVN-vlp, and PVN-pm) of the PVN (Figure 5) and in central SFO (Figure 6) in VEH-treated HF rats compared with VEH-treated sham-operated rats. In the sham-operated rats, AT1-R immunoreactivity was located predominantly in the PVN-mp. In HF rats, AT1-R immunoreactivity was more pronounced in PVN-mp, but the PVN-dp, PVN-vlp, and PVN-pm also exhibited distinct increases in AT1-R immunoreactivity. In the SFO, HF rats displayed increased AT1-R expression throughout compared with sham-operated rats. Immunofluorescent studies with a different AT1-R antibody (SC-1173; Santa Cruz Biotechnology) were performed to confirm these patterns of distribution in PVN and SFO (Figure S1).
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P<0.05, PVN-mp compared with other PVN regions, Sham+VEH.
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HF rats treated with ICV losartan, the p44/42 inhibitor PD98059, and the JNK inhibitor SP600125 for 4 weeks had less AT1-R immunoreactivity in all 4 regions of PVN (Figure 5) and in SFO (Figure 6) than VEH-treated HF rats. ICV infusion of the p38 MAPK inhibitor SB203580 had no significant effect on the AT1-R expression in the PVN or SFO of HR rats.
Indicators of HF
Echocardiography at baseline demonstrated that HF animals in the immunohistochemistry study groups assigned to treatment with AT1-R antagonists and MAPK inhibitors versus VEH were well-matched with regard to left ventricular (LV) systolic function (Table). Compared with sham-operated rats, HF rats had a significantly lower LV ejection fraction and a significantly higher LV end-diastolic volume.
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Hemodynamic assessment of these rats at the completion of the treatment protocol revealed that VEH-treated HF rats had a lower LV peak systolic pressure and maximal rate of rise of LV systolic pressure (LV dP/dt max) and a higher LV end diastolic pressure than VEH-treated sham-operated rats. The right ventricular weight/body weight ratio was substantially higher in VEH-treated HF compared with VEH-treated sham-operated rats.
HF rats treated for 4 weeks with the AT1-R antagonist and the MAPK inhibitors had higher LV dP/dt max, lower LV end- diastolic pressure, and a lower right ventricular weight/body weight ratio than VEH-treated HF rats, but all of these values were still significantly different from VEH-treated sham-operated rats (Table). There were no differences in any of these variables related to the specific MAPK inhibitor infused. LV peak systolic pressure was not significantly different in drug-treated versus VEH-treated HF.
Protocol II: Acute ICV Infusion of Losartan and MAPK Inhibitors
Molecular Studies
Real-time polymerase chain reaction demonstrated higher AT1-R mRNA expression in both PVN and SFO (Figure 7) of VEH-treated HF rats 4 weeks after coronary ligation compared with VEH-treated sham-operated rats. A 3-hour ICV infusion of losartan in these rats with otherwise untreated HF resulted in a significantly lower AT1-R mRNA level in both PVN and SFO (Figure 7). A 3-hour ICV infusion of the p44/42 inhibitors PD98059 or the JNK inhibitor SP600125 also resulted in a lower AT1-R mRNA level in PVN and SFO. A 3-hour ICV infusion of the p38 MAPK inhibitor SB203580 had no effect on AT1-R mRNA level in PVN or SFO (Figure 7).
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Indicators of HF
Baseline echocardiography revealed no differences in LV systolic function in sham-operated or HF rats assigned to acute ICV treatment with VEH, losartan, or the MAPK inhibitors (Table S1). A 3-hour ICV infusion of losartan or the MAPK inhibitors had no effect on LV variables of dP/dtmax, LV end diastolic pressure, and LV peak systolic pressure or on right ventricular weight/body weight ratio compared with VEH-treated HF rats 4 weeks after coronary ligation (Table S1). For further details, please see the online supplement.
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Discussion |
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Novel findings of this study are: (1) MAPK signaling pathways are activated in PVN and SFO of HF rats, concomitant with increases in AT1-R mRNA and AT1-R protein in these regions; (2) an AT1-R antagonist reduces the expression of p-p44/42 MAPK, JNK, and p38 MAPK in PVN and SFO in HF rats; and (3) either central inhibition of p44/42 MAPK and JNK activity or AT1-R blockade prevents upregulation of AT1-R mRNA and protein in HF rats at sites both inside (PVN) and outside (SFO) the blood–brain barrier.
In animal models of HF, upregulation of brain RAS activity and subsequent Ang II–dependent stimulation of reduced nicotinamide-adenine dinucleotide phosphate oxidase–dependent superoxide production contribute significantly to increased sympathetic nerve activity.19 An important and poorly understood aspect of this process is the upregulation of the AT1-R that mediates most of the known effects of Ang II. In normal animals9 and in animals with HF,6 an excess of Ang II appears to upregulate its own receptor in the brain. A putative explanation for this seemingly counterintuitive observation is that Ang II triggers MAPK signaling pathways that increase the expression of c-Fos and c-Jun, the primary components of the transcription factor AP-1.20 AP-1 binding sequences have been identified in the regulatory region of the AT1-R gene,16 and transactivation of AP-1 has been implicated recently in upregulation of the AT1-R in HF.6
A recent study6 supported that hypothesis, demonstrating Ang II–dependent upregulation of AT1-R with concomitant c-Jun and JNK protein phosphorylation in the rostral ventrolateral medulla in rabbits with HF and normal rabbits infused with ICV Ang II and inhibition of Ang II–induced expression of AT1-R by losartan or a JNK inhibitor in neuronal cell cultures. Here, we expand on that observation, demonstrating in vivo that chronic ICV infusion of a JNK inhibitor or a p44/42 MAPK inhibitor reduces AT1-R expression in the PVN and SFO in rats with HF. Losartan has a similar effect on AT1-R expression while reducing phosphorylation of p44/42 MAPK and JNK. These observations are consistent with the hypothesis that Ang II, acting on the AT1-R to activate the MAPK pathway, is at least one stimulus inducing the upregulation of the AT1-R in PVN and SFO in HF. The present study does not exclude the possibility that Ang II and MAPK upregulate AT1-R by parallel and independent mechanisms. However, in unpublished work,21 we found that a chronic systemic infusion of Ang II, subthreshold to raise arterial pressure or plasma aldosterone, upregulates AT1-R in SFO and PVN in normal rats; that effect is blocked by a chronic ICV infusion of p44/42 MAPK or JNK inhibitors. In a recent study,22 we demonstrated functional significance of the MAPK pathway, with the p44/42 MAPK inhibitors reducing sympathetic drive in HF and the p44/42 MAPK inhibitor blocking pressor responses to ICV Ang II. Thus, the available evidence supports the hypothesis that Ang II activation of MAPK contributes to upregulation of the AT1-R. Other mechanisms that affect the MAPK pathway (eg, proinflammatory cytokines, aldosterone) and other mechanisms activated by Ang II (eg, reactive oxygen species) may also contribute.
The source of Ang II presumably driving the MAPK pathway was not identified in this study. Blood-borne Ang II is increased in this model of HF,23 making the circulation a likely source of Ang II to activate AT1-R signaling pathways in the SFO. In HF, angiotensin-converting enzyme activity is increased in the SFO24 and the PVN,7 making local production of Ang II a likely possibility at both sites. Another potential source might be angiotensinergic projections from the circumventricular organs to PVN,25 activated by either circulating or locally produced Ang II or both. For example, microinjection of Ang II into SFO induces a 10-fold increase in Ang II release in PVN in the rat.26 Regardless of the source of Ang II, the Ang II–dependent signaling mechanisms upregulating AT1-R appear to be the same in both regions.
An intriguing finding of this study is the diffuse distribution of AT1-R throughout the PVN in HF rats. In normal unstressed rats,27 AT1-R are found primarily in PVN-mp, where they are associated with neuroendocrine (corticotropin releasing hormone) neurons. We observed a similar distribution in sham-operated rats, in which AT1-R were highly expressed in the PVN-mp subdivision, much less so in the PVN-dp, PVN-vlp, and PVN-pm subdivisions. In the HF rats, AT1-R expression was pronounced not only in PVN-mp but also in the PVN-dp and PVN-vlp, and even in the magnocellular neurons in PVN-mp which do not normally express AT1-R.5 A similar general broadening of the distribution of AT1-R immunoreactivity was noted in the SFO in HF rats.
In the HF setting, in which the brain RAS is activated, these observations are not surprising. They are consistent with the known functions of the PVN in HF. Plasma levels of arginine vasopressin, a downstream product of the RAS, are increased in HF; the presence of Ang II has been shown to induce the expression of AT1-R in magnocellular neurons of the PVN,8 a major source of arginine vasopressin. Local inhibition of AT1-R in the PVN reduces sympathetic activation in HF rats,28 presumably by influencing presympathetic neurons in the PVN-dp and PVN-vlp.29 Clearly, the actions of Ang II in the PVN of HF rats extend beyond regulation of corticotropin releasing hormone. Upregulation of AT1-R expression in regions in which they are not normally expressed may be a mechanism for recruiting autonomic and neuroendocrine neurons in response to the stress of HF. Increases in sympathetic nerve activity and plasma vasopressin, in addition to the increases in circulating corticosterone and epinephrine resulting from activation of the hypothalamic-pituitary-adrenal axis, are typical responses to stress. Of particular interest is the observation that the pattern of p-p44/42 and p-JNK expression matches the pattern of AT1-R expression in the PVN and SFO in both sham-operated and HF rats, lending credence to their role in upregulating the AT1-R.
The improvements in LV systolic function (LV dP/dtmax) and volume regulation (LV end-diastolic pressure) observed in this study likely reflect a centrally mediated reduction in sympathetic drive. Similar improvements have been demonstrated in previous studies in which the RAS has been manipulated selectively at the central nervous system level.30–33 Supporting that interpretation are recent studies22 from our laboratory demonstrating that acute administration of the p44/42 MAPK inhibitors reduces renal sympathetic nerve activity in rats with HF but not in sham-operated controls. The opposite interpretation might be entertained, ie, that the changes we observed in hypothalamic AT1-R expression resulted from treatment-induced improvement in LV systolic function. Two observations counter that argument: (1) chronic infusion of the p38 MAPK inhibitor had similar salutary effects on LV dysfunction without affecting the hypothalamic expression of AT1-R; and (2) acute ICV infusions of the inhibitors reduced AT1-R mRNA in the absence of any change in LV function.
Finally, the mechanism by which the p38 MAPK inhibitor improves the peripheral dynamics of HF without affecting hypothalamic AT1-R expression is not explained by these studies. However, p38 MAPK has been implicated in a variety of signaling pathways that may contribute to sympathetic activity in this setting.34
A limitation of this study is that the indices of HF were measured in 2 subsets of the rats studied (those used for the immunohistochemical and the real-time polymerase chain reaction measurements) but not in those used for Western blot assessment of protein levels. However, in this and in previous studies,30,31 the method for induction of HF results in a reproducible degree of LV dysfunction.
Perspectives
The present study provides strong evidence from an in vivo model that the increased Ang II resulting from activation of the RAS in HF upregulates its own receptor in the brain by activating MAPK signaling pathways. The same feed-forward mechanism appears to affect central neurons inside and outside the blood–brain barrier, suggesting that Ang II produced by both the systemic RAS and the brain RAS may contribute. Other neurochemical mediators that are present in the HF brain (eg, aldosterone35 and proinflammatory cytokines36,37) can activate these same intracellular signaling pathways and may contribute to upregulation of AT1-R.38,39 Thus, MAPK signaling may provide a substrate for central interactions between other excitatory mediators and the RAS in HF.
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Acknowledgments |
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Sources of Funding
This work was supported by a Merit Review award (R.B.F.) from the Department of Veterans Affairs, National Institutes of Health grant RO1HL073986 (R.B.F.), and institutional funds provided by the University of Iowa.
Disclosures
None.
Received March 17, 2008; first decision April 4, 2008; accepted July 1, 2008.
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