Angiotensin II-mediated posttranslational modification of nNOS in the PVN of rats with CHF: role for PIN

Sharma, Neeru M.; Llewellyn, Tamra L.; Zheng, Hong; Patel, Kaushik P.

doi:10.1152/ajpheart.00170.2013

Cited by 33 publications

(59 citation statements)

References 43 publications

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“…GFAP is a marker of terminally differentiated astrocytes, however, and almost all studies of astrocyte development rely on GFAP expression (1,33). Third, we did not evaluate other brain sites, such as the paraventricular nucleus of the hypothalamus, that are important for activation of the sympathetic nervous system in heart failure (25,41). We cannot exclude the possibility that other areas in the brain are similarly altered in heart failure.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

Isegawa

Hirooka

Katsuki

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Isegawa K, Hirooka Y, Katsuki M, Kishi T, Sunagawa K. Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure. Am J Physiol Heart Circ Physiol 307: H1448 -H1455, 2014. First published September 12, 2014 doi:10.1152/ajpheart.00462.2014.-Enhanced central sympathetic outflow worsens left ventricular (LV) remodeling and prognosis in heart failure after myocardial infarction (MI). Previous studies suggested that activation of brain angiotensin II type 1 receptors (AT 1R) in the brain stem leads to sympathoexcitation due to neuronal AT 1R upregulation. Recent studies, however, revealed the importance of astrocytes for modulating neuronal activity, but whether changes in astrocytes influence central sympathetic outflow in heart failure is unknown. In the normal state, AT1R are only weakly expressed in astrocytes. We hypothesized that AT1R in astrocytes are upregulated in heart failure and modulate the activity of adjacent neurons, leading to enhanced sympathetic outflow. In the present study, by targeting deletion of astrocyte-specific AT 1R, we investigated whether AT1R in astrocytes have a key role in enhancing central sympathetic outflow, and thereby influencing LV remodeling process and the prognosis of MI-induced heart failure. Using the Cre-LoxP system, we generated glial fibrillary acidic protein (GFAP)-specific AT1R knockout (GFAP/ AT 1RKO) mice. Urinary norepinephrine excretion for 24 h, as an indicator of sympathoexcitation, was significantly lower in GFAP/ AT 1RKO-MI mice than in control-MI mice. LV size and heart weight after MI were significantly smaller in GFAP/AT 1RKO mice than in control mice. Prognosis was significantly improved in GFAP/ AT 1RKO-MI mice compared with control-MI mice. Our findings indicated that AT 1R expression was upregulated in brain stem astrocytes in MI-induced heart failure, which worsened LV remodeling and prognosis via sympathoexcitation. Thus, in addition to neuronal AT 1R, AT1R in astrocytes appear to have a key role in enhancing central sympathetic outflow in heart failure.astrocyte; angiotensin II type 1 receptor; sympathetic nervous system; heart failure ENHANCED central sympathetic outflow is a cardinal manifestation of heart failure, which influences the left ventricular (LV) remodeling process and eventually worsens prognosis (10, 45). Activation of brain angiotensin II type 1 receptors (AT 1 R) enhances sympathetic outflow in experimental heart failure (12, 13, 30). Furthermore, activation of AT 1 R has a major role in the production of reactive oxygen species (ROS) in the brain stem and hypothalamus (5, 17). For example, ROS blockade in the central nervous system by intracerebroventricular injection of superoxide dismutase or tempol prevents sympathoexcitation after myocardial infarction (MI) (19). In particular, AT 1 Rinduced ROS production in the rostral ventrolateral medulla (RVLM) contributes to enhance the sympathetic outflow in heart failure (12, 13). Previou...

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Section: Discussionmentioning

confidence: 99%

Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

Isegawa

Hirooka

Katsuki

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Impaired NO signaling because of nNOS uncoupling and oxidative stress was recently observed in the cerebral artery of Zucker obese rats 53 and in penile arteries under conditions of insulin resistance. 54 PIN was demonstrated in a recent study 55 to decrease the catalytically active dimeric nNOS via ubiqutin-dependent proteolytic degradation of the enzyme in the brain. Whether this modification of nNOS activity by PIN contributes to ROS generation under the condition of MetS awaits further investigation.…”

Section: Discussionmentioning

confidence: 97%

Role of Nitric Oxide Synthase Uncoupling at Rostral Ventrolateral Medulla in Redox-Sensitive Hypertension Associated With Metabolic Syndrome

Chao

Tsay

et al. 2014

Hypertension

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Metabolic syndrome (MetS), which is rapidly becoming prevalent worldwide, is long known to be associated with hypertension and recently with oxidative stress. Of note is that oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, contributes to sympathoexcitation and hypertension. This study sought to identify the source of tissue oxidative stress in RVLM and their roles in neural mechanism of hypertension associated with MetS. Adult normotensive rats subjected to a high-fructose diet for 8 weeks developed metabolic traits of MetS, alongside increases in sympathetic vasomotor activity and blood pressure. In RVLM of these MetS rats, the tissue level of reactive oxygen species was increased, nitric oxide (NO) was decreased, and mitochondrial electron transport capacity was reduced. Whereas the protein expression of neuronal NO synthase (nNOS) or protein inhibitor of nNOS was increased, the ratio of nNOS dimer/monomer was significantly decreased. Oral intake of pioglitazone or intracisternal infusion of tempol or coenzyme Q 10 significantly abrogated all those molecular events in high-fructose diet–fed rats and ameliorated sympathoexcitation and hypertension. Gene silencing of protein inhibitor of nNOS mRNA in RVLM using lentivirus carrying small hairpin RNA inhibited protein inhibitor of nNOS expression, increased the ratio of nNOS dimer/monomer, restored NO content, and alleviated oxidative stress in RVLM of high-fructose diet–fed rats, alongside significantly reduced sympathoexcitation and hypertension. These results suggest that redox-sensitive and protein inhibitor of nNOS–mediated nNOS uncoupling is engaged in a vicious cycle that sustains the production of reactive oxygen species in RVLM, resulting in sympathoexcitation and hypertension associated with MetS.

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“…For example, it has long been recognized that in congestive heart failure, another pathology associated with activated RAS (68), increased sympathetic nerve activity is associated with pro-excitatory and blunted NO-mediated inhibitory adaptations in PVN neurons (40,76). Notably, these maladaptations are reversible after blockade of AT1R (36,58). These observations could suggest a putatively nonspecific role played by heightened RAS activation/ANG II signaling in enhancing PVN neuronal stress reactivity.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells

Saxena

Bachelor

Park

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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We previously reported that in the rodent, a model of dilutional hyponatremia associated with hepatic cirrhosis, TRPV4 expression is increased in lipid rafts from the hypothalamus and that this effect may be angiotensin dependent. In this study, we utilized the immortalized neuroendocrine rat hypothalamic 4B cell line to more directly test the effects of angiotensin II (ANG II) on TRPV4 expression and function. Our results demonstrate the expression of corticotropin-releasing factor (CRF) transcripts, for sex-determining region Y (SRY) (male genotype), arginine vasopressin (AVP), TRPV4, and ANG II type 1a and 1b receptor in 4B cells. After a 1-h incubation in ANG II (100 nM), 4B cells showed increased TRPV4 abundance in the plasma membrane fraction, and this effect was prevented by the ANG II type 1 receptor antagonist losartan (1 M) and by a Src kinase inhibitor PP2 (10 M). Ratiometric calcium imaging experiments demonstrated that ANG II incubation potentiated TRPV4 agonist (GSK 1016790A, 20 nM)-induced calcium influx (control 18.4 Ϯ 2.8% n ϭ 5 and ANG II 80.5 Ϯ 2.4% n ϭ 5). This ANG II-induced increase in calcium influx was also blocked by 1 M losartan and 10 M PP2 (losartan 26.4 Ϯ 3.8% n ϭ 5 and PP2 19.7 Ϯ 3.9% n ϭ 5). Our data suggests that ANG II can increase TRPV4 channel membrane expression in 4B cells through its action on AT1R involving a Src kinase pathway.angiotensin; TRPV4; hypothalamus; 4B; SRC kinase; SRY TRANSIENT RECEPTOR POTENTIAL (TRP) channel superfamily plays a central role in sensory physiology (47, 54). The TRP subfamily vanilloid member 4 (TRPV4) is a nonselective cation channel that is calcium permeable and shows polymodal activation by diverse stimuli including, but not limited to, moderate heat, cell swelling, and endogenous ligands (51,55,69). Functionally, it is strongly implicated in a number of physiological systems that include endothelial function and vascular tone (21, 64), renal function (56), central osmosensation (41, 46), and regulating hydromineral homeostasis (51, 55, 69). Mutations of TRPV4 are linked to a number of motor and sensory neuropathies and skeletal dysplasias (51, 69).TRPV4 is expressed in central nervous system (CNS) regions involved in neuroendocrine function including neurosecretory cells in the supraoptic nucleus (SON) and the paraventricular nuclei of the hypothalamus (PVN) (3, 9). In a rodent model of cirrhosis, we have previously reported increased TRPV4 trafficking to lipid rafts in hypothalamic samples that contained the SON, the PVN, and the organum vasculosum of the lamina terminalis (9). Importantly, we also found that increased TRPV4 trafficking correlated with activation of renin-angiotensin system (RAS) and was reversed after RAS inhibition (9).Angiotensin II (ANG II) is an effector molecule of RAS (25). Circulating ANG II is known to contribute to water and electrolyte homeostasis peripherally and centrally through its actions on blood-brain barrier-deficient circumventricular organs in the forebrain and dorsal hindbrain (31, 43). As part of the ...

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Angiotensin II-mediated posttranslational modification of nNOS in the PVN of rats with CHF: role for PIN

Cited by 33 publications

References 43 publications

Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure

Role of Nitric Oxide Synthase Uncoupling at Rostral Ventrolateral Medulla in Redox-Sensitive Hypertension Associated With Metabolic Syndrome

Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells

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