Chronic Blockade of Phosphatidylinositol 3-Kinase in the Nucleus Tractus Solitarii Is Prohypertensive in the Spontaneously Hypertensive Rat

Zubcevic, Jasenka; Waki, Hidefumi; Díez-Freire, Carlos; Gampel, Alexandra; Raizada, Mohan K.; Paton, Julian F. R.

doi:10.1161/hypertensionaha.108.122341

Cited by 16 publications

(18 citation statements)

References 54 publications

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“…16,17 For example, the enzyme phosphoinositide 3-kinase (PI3K), thought to be involved in Ang-II-mediated neuronal signaling, is elevated in the NTS and paraventricular nucleus (PVN) of SHR. 17,18 However, chronic neuronal blockade of PI3K in the NTS is prohypertensive, 17 whereas it is antihypertensive in the PVN of SHR. 18 Similarly, chronic silencing of catecholaminergic neurons in the NTS increases BP more profoundly in the SHR.…”

Section: Discussionmentioning

confidence: 99%

Nucleus of the Solitary Tract (Pro)Renin Receptor-Mediated Antihypertensive Effect Involves Nuclear Factor-κB-Cytokine Signaling in the Spontaneously Hypertensive Rat

et al. 2013

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622( P ro)renin receptor (PRR) is highly expressed in many tissues, including those of the heart and brain, 1,2 and plays an important role in the maintenance of cardiovascular homeostasis in the periphery. 3,4 However, the role of PRR in the brain remains poorly understood. Despite intrinsically low renin concentrations in the brain, the ability of renin to signal in a similar manner to angiotensin (Ang)-II, 5 coupled with the presence of PRR in the brain cardioregulatory areas, 2,6 suggests a role for PRR in central cardiovascular control. Our previous study revealed that PRR expression is significantly increased in the nucleus of the solitary tract (NTS) and the supraoptic nucleus (SON) of spontaneously hypertensive rats (SHR) compared with normotensive Wistar Kyoto (WKY) controls. 6 Genetic knockdown of PRR in the SHR SON 6 and other cardioregulatory regions, such as the subfornical organ (SFO) 7 in hypertensive rats, resulted in a reduction of blood pressure (BP). However, the role of NTS PRR in BP control and its precise mechanisms remain elusive.Our interest in the role of NTS PRR derives from the following: (1) The NTS is the central termination site of baroreceptor input, regulating both the set-point of arterial pressure and the gain of the baroreflex, mechanisms essential for short-and long-term homeostatic control of arterial pressure 8,9 ; (2) In the hypertensive model, the NTS exhibits an abnormal inflammatory state because the expression of many inflammatory mediators known to be involved in modulating synaptic transmission, including interleukin (IL)-6 and C-C motif ligand 5 (Ccl5), are downregulated in the SHR NTS compared with the WKY rats 10,11 ; and (3) PRR mRNA in the SHR NTS is significantly increased compared with the WKY rats. 6 We propose that altered activity of PRR in the NTS is linked to hypertension, and that the NTS PRR regulates BP Abstract-The importance of the (pro)renin receptor (PRR) in the function of the central nervous system is increasingly evident because PRR seems to play a role in neuronal control of cardiovascular function. PRR expression is elevated in the nucleus of the solitary tract (NTS) of spontaneously hypertensive rats (SHR).In this study, we tested the hypothesis that altered activity of PRR in the NTS is linked to hypertension. Eight weeks of chronic knockdown of the NTS PRR, using recombinant adeno-associated virus type 2 (AAV2)-PRR-small hairpain RNA (shRNA)-mediated gene transduction, caused a significant increase in mean arterial pressure (MAP) in the SHR (shRNA, 173±5; Control, 151±6 mm Hg) but not in Wistar Kyoto rats (shRNA, 108±7; Control, 106±6 mm Hg). The MAP elevation in the SHR was associated with decreased inflammatory markers tumor necrosis factor-α, interleukin-6, C-C motif ligand 5, and their transcription factor, nuclear factor-κB. Consistent with the pressor effects of the PRR knockdown, acute bilateral NTS injection of human renin (2 pmol/side) decreased MAP and heart rate (HR) in SHR (ΔMAP, −38±4 mm Hg; Δheart rate, −40±10 bp...

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Section: Discussionmentioning

confidence: 99%

Nucleus of the Solitary Tract (Pro)Renin Receptor-Mediated Antihypertensive Effect Involves Nuclear Factor-κB-Cytokine Signaling in the Spontaneously Hypertensive Rat

et al. 2013

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“…of four to five observations. Symbols denote statistical significance (P Ͻ 0.05) based on comparing the responses elicited by WIN55,212-2 alone or in the presence of the pharmacological intervention versus vehicle as well as treatment control, AM251,wortmannin,or PD98059 values. tive PI3K in the spontaneously hypertensive rat (Veerasingham et al, 2005) in the NTS (Zubcevic et al, 2009) and the RVLM (Seyedabadi et al, 2001) elicits pressor and depressor response, respectively. Furthermore, insulin enhancement of NTS Akt phosphorylation causes hypotension in normotensive rats (Huang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, PI3K/Akt activation evokes a depressor response and underlies the hypotensive response elicited by intra-NTS insulin (Huang et al, 2004). It is noteworthy that PI3K signaling is up-regulated in central cardiovascular regulatory areas in the brainstem (RVLM and NTS) and hypothalamus of hypertensive rats (Veerasingham et al, 2005;Zubcevic et al, 2009). Collectively, the role of PI3/Akt-ERK signaling in mediating a blood pressure response seems to depend, at least partly, on the type of the targeted receptor within the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Differential Modulation of Brainstem Phosphatidylinositol 3-Kinase/Akt and Extracellular Signal-Regulated Kinase 1/2 Signaling Underlies WIN55,212-2 Centrally Mediated Pressor Response in Conscious Rats

Ibrahim

Abdel‐Rahman²

2011

J Pharmacol Exp Ther

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Our recent study demonstrated that central cannabinoid receptor 1 (CB 1 R) activation caused dose-related pressor response in conscious rats, and reported studies implicated the brainstem phosphatidylinositol 3-kinase (PI3K)/Akt-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in blood pressure control. Therefore, in this study, we tested the hypothesis that the modulation of brainstem PI3K/Akt-ERK1/2 signaling plays a critical role in the central CB 1 Rmediated pressor response. In conscious freely moving rats, the pressor response elicited by intracisternal (i.c.)-(1-naphthalenyl) methanone mesylate salt (WIN55,212-2) (15 g) was associated with significant increases in ERK1/2 phosphorylation in the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS). In contrast, Akt phosphorylation was significantly reduced in the same neuronal pools. Pretreatment with the selectiveattenuated the neurochemical responses elicited by central CB 1 R activation. Furthermore, pretreatment with the ERK/mitogenactivated protein kinase kinase inhibitor 2Ј-amino-3Ј-methoxyflavone (PD98059) (5 g i.c.) abrogated WIN55,212-2-evoked increases in blood pressure and neuronal ERK1/2 phosphorylation but not the reduction in Akt phosphorylation. On the other hand, prior PI3K inhibition with wortmannin (0.4 g i.c.) exacerbated the WIN55,212-2 (7.5 and 15 g i.c.) dose-related increases in blood pressure and ERK1/2 phosphorylation in the RVLM. The present neurochemical and integrative studies yield new insight into the critical role of two brainstem kinases, PI3K and ERK1/2, in the pressor response elicited by central CB 1 R activation in conscious rats.

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“…4.3 software (Data Sciences International). Spectral analysis of the SBP and pulse interval waveforms was performed as previously described using the Hey Presto software [28,29]. …”

Section: Methodsmentioning

confidence: 99%

Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure

et al. 2018

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Recent evidence indicates a link between gut pathology and microbiome with hypertension (HTN) in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in the present study were to test the hypotheses that high blood pressure (BP) patients have distinct gut microbiomes and that gut–epithelial barrier function markers and microbiome composition could predict systolic BP (SBP). Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high BP and reference subjects. Significant increases in plasma of intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), and augmented gut-targetting proinflammatory T helper 17 (Th17) cells in high BP patients demonstrated increased intestinal inflammation and permeability. Zonulin, a gut epithelial tight junction protein regulator, was markedly elevated, further supporting gut barrier dysfunction in high BP. Zonulin strongly correlated with SBP (R2 = 0.5301, P<0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome data and circulating markers of gut health, and validated in a separate cohort by prediction of SBP from zonulin in plasma (R2 = 0.4608, P<0.0001). The mouse model of HTN, chronic angiotensin II (Ang II) infusion, was used to confirm the effects of butyrate and gut barrier function on the cardiovascular system and BP. These results support our conclusion that intestinal barrier dysfunction and microbiome function are linked to HTN in humans. They suggest that manipulation of gut microbiome and its barrier functions could be the new therapeutic and diagnostic avenues for HTN.

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Chronic Blockade of Phosphatidylinositol 3-Kinase in the Nucleus Tractus Solitarii Is Prohypertensive in the Spontaneously Hypertensive Rat

Cited by 16 publications

References 54 publications

Nucleus of the Solitary Tract (Pro)Renin Receptor-Mediated Antihypertensive Effect Involves Nuclear Factor-κB-Cytokine Signaling in the Spontaneously Hypertensive Rat

Nucleus of the Solitary Tract (Pro)Renin Receptor-Mediated Antihypertensive Effect Involves Nuclear Factor-κB-Cytokine Signaling in the Spontaneously Hypertensive Rat

Differential Modulation of Brainstem Phosphatidylinositol 3-Kinase/Akt and Extracellular Signal-Regulated Kinase 1/2 Signaling Underlies WIN55,212-2 Centrally Mediated Pressor Response in Conscious Rats

Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure

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