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

Abstract

Abstract-We have previously reported that the expression of Angiotensin II (Ang II) type 1 receptors (AT1R) was increased in the rostral ventrolateral medulla (RVLM) of rabbits with chronic heart failure (CHF) and in the RVLM of normal rabbits infused with intracerebroventricular (ICV) Ang II. The present study investigated whether oxidant stress plays a role in Ang II-induced AT1R upregulation and its relationship to the transcription factor activator protein 1 (AP1) in CHF rabbits and in the CATHa neuronal cell line. Key Words: angiotensin ii Ⅲ antioxidant enzymes Ⅲ brain Ⅲ c-jun Ⅲ c-Jun NH2-terminal kinase A ngiotensin II (Ang II), the principle mediator of the renin-angiotensin system, plays a pivotal role in cardiovascular and renal homeostasis. Most of the physiological and pathophysiological effects of Ang II are mediated by the Angiotensin II type 1 receptor (AT1R). The activation of the renin-angiotensin system and the sympathetic nervous system in chronic heart failure (CHF) are critical factors that contribute to the development and progression of CHF in patients. 1,2 Evidence also demonstrates that AT1R blockers, when added to conventional treatment for patients with CHF, are associated with a reduction in morbidity and mortality as well as an improvement in quality of life. 3 Currently, blockade of the renin-angiotensin system has become the primary treatment for patients with CHF. Therefore, a comprehensive understanding of the regulation of the AT1R is necessary for developing new therapies to target this receptor in the setting of CHF.The role of reactive oxygen species (ROS) in the cardiovascular system has been investigated extensively over the past decade. 4 It has been reported that, in the rostral ventrolateral medulla (RVLM), the levels of ROS are elevated in stroke-prone spontaneously hypertensive rats. Scavenging superoxide anion (O 2•Ϫ ) in the RVLM reduces both sympathetic nerve activity and blood pressure. 5 Similar evidence has been provided for rabbits with CHF. 6 Ang II induces a rapid and transient increase in ROS in a wide variety of cell types. 7 Ang II-induced ROS-formation is attenuated by the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI), suggesting that it is mediated through NADPH Oxidase. 7 In addition, Ang II-induced ROS-formation can also be blocked by losartan, 8 suggesting that AT1R and its downstream pathway are involved.However, the downstream targets of ROS have remained largely unexplored, at least for the regulation of the AT1R. Extracellular administration of nonlethal concentrations of H 2 O 2 has been demonstrated to activate mitogen-activated protein kinase (MAPK) as well as the c-Jun amino-terminal kinase (JNK). 9 Endogenous ROS induced by Ang II has also been shown to activate stress activated protein kinase (SAPK), which can be inhibited by treating cells with Original

Angiotensin II regulates ACE and ACE2 in neurons through p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 signaling

“…We did not measure AT 1 R and AT 2 R expression in the current study. Our previous work clearly showed that ANG II upregulates AT 1 R transcription and protein expression at 100 nM within 4 h in this neuronal cell line (21,22). Recent work by Herrera et al (11) has called into question the validity of AT 1 R measurements, at least in mice, because of nonspecificity of commercial antibodies.…”

“…The Src family of protein tyrosine kinases has been shown to play a key role in the coupling of cell surface receptors with MAPK activation (14,27) and NADPH oxidase-derived O 2 ·Ϫ , which also serves as a second messenger downstream of the AT 1 R for MAPK activation (5,14). Our laboratory has shown that ANG II induces O 2 ·Ϫ production through AT 1 R and NADPH oxidase activation in CATH.a neurons (21). Therefore, O 2 ·Ϫ may also participate in the regulation of ACE and ACE2 expression.…”

Oxidative Stress Causes Renal Angiotensin II Type 1 Receptor Upregulation, Na + /H + Exchanger 3 Overstimulation, and Hypertension

“…1,30 The novel aspect of this study is that it elucidates the mechanism for Ang II-mediated NHE3 stimulation. We demonstrate that, in BSO-treated rats, which exhibit oxidative stress and high blood pressure, the Ang II-induced NHE3 stimulation is significantly higher than normotensive rats.…”

“…31 Nevertheless, these data confirm previous findings that oxidative stress could be an independent risk factor to the development of hypertension by exaggerating AT 1 R expression, response, and stimulation of renal sodium transporters. 1,30,[32][33][34] Ang II via AT 1 Rs activates serine/threonine and tyrosine kinase pathways, both of which can regulate NHE3 activity. 1,15,20,28 The serine/threonine kinases are activated via PLC stimulation, and our data show that D609 and ET-18-OCH3 (PLC inhibitors) abolished Ang II-induced NHE3 stimulation, indicating the involvement of PLC pathways.…”

Vascular and Central Activation of Peroxisome Proliferator–Activated Receptor-β Attenuates Angiotensin II–Induced Hypertension: Role of RGS-5

“…How PPARb activation reduces AT 1 expression remains unknown. Several reports have demonstrated that AngII in the rostral ventrolateral medulla induced long-term pressor actions via upregulation of the AT 1 receptor gene in a series of molecular events involving O 2 2 production from NADPH oxidase after AT 1 receptor activation (Chan et al, 2007;Liu et al, 2008). We found that chronic activation of PPARb increased RGS5 expression, which also interfered with the AngII-AT 1 signaling pathway in the brain, reducing NADPH oxidase activity and the subsequent AT 1 receptor overexpression, suggesting an important role of brainstem RGS5 in the antihypertensive effects of oral GW0742 in AngII-induced hypertension.…”