Defective Phosphatidylinositol 3-Kinase Signaling in Central Control of Cardiovascular Effects in the Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats

Hsiao, Michael; Lu, Pei Jung; Huang, Hsiao Ning; Lo, Wan Chen; Ho, Wen Yu; Lai, Tsung‐Ching; Chiang, Hung; Tseng, Ching Jiunn

doi:10.1291/hypres.31.1209

Cited by 10 publications

(7 citation statements)

References 25 publications

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“…Indeed, others have shown in other animal models of hypertension that increased levels of PI3K subunits and PI3K activity did not necessarily lead to elevation of PKB/Akt signaling,41 suggesting the presence of a PI3K-dependent but a PKB/Akt-independent signaling pathway. A recent study also revealed that baseline phosphorylated (but not total) PKB/Akt levels are lower in the NTS of SHRs compared with the WKY rats 42. These authors also showed that injection of phosphoinositide(3,4,5)P 3 (a phospholipids second messenger produced by PI3K, thereby mimicking activation of PI3K) in the NTS of the SHR failed to activate the downstream PKB/Akt but produced cardiovascular responses that are in full agreement with the findings of our present study (ie, depressor action).…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2009

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Abstract-Phosphatidylinositol 3-kinase (PI3K) within brain stem neurons has been implicated in hypertension in the spontaneously hypertensive rat (SHR). Previously, we demonstrated elevated expression of PI3K subunits in rostral ventrolateral medulla and paraventricular nucleus of SHRs compared with Wistar-Kyoto rats. Here, we considered expression levels of PI3K in the nucleus tractus solitarii, a pivotal region in reflex regulation of arterial pressure, and determined its functional role for arterial pressure homeostasis in SHRs and Wistar-Kyoto rats. We found elevated mRNA levels of p110␤ and p110␦ catalytic PI3K subunits in the nucleus tractus solitarii of adult (12 to 14 weeks old) SHRs relative to the age-matched Wistar-Kyoto rats (fold differences relative to ␤-actin: Key Words: hypertension Ⅲ brain stem Ⅲ NTS Ⅲ PI3K Ⅲ baroreflex control T he pathogenesis of essential hypertension is multifactorial. In a majority of hypertensive cases, the underlying causes remain unknown and are most probably a product of complex interactions between susceptibility genes and environmental factors influencing neural, humoral, cellular, and subcellular mechanisms. 1-3 Both animal 4 -7 and human studies 8 -11 suggest that overactive sympathetic nerve activity participates in the pathogenesis of hypertension. In a rat model of genetic hypertension (the spontaneously hypertensive rat [SHR]), sympathetic nerve activity is significantly higher in comparison with its normotensive control, the Wistar-Kyoto (WKY) rat. 6 Interestingly, this raised level of activity precedes the onset of hypertension in this animal model, supporting a causative role in the development of this pathology. 11 However, the roles of brain regions and intracellular signaling pathways in the pathogenesis of chronic sympathetic overactivity and hypertension are not fully understood. Our previous studies have demonstrated an elevated phosphatidylinositol 3-kinase (PI3K) signaling in presympathetic brain regions of the SHR. 12,13 We found that the mRNA levels of specific class I PI3K subunits (p85␣, p110␣, and p110␦) were elevated within the rostral ventrolateral medulla (RVLM) and paraventricular nucleus of the SHRs compared with the WKY rats, which was accompanied by increased PI3K activity in brain stem/hypothalamic neuronal cultures made from SHRs. 13 In addition, acute PI3K inhibition within the RVLM decreased blood pressure (BP) in the anesthetized SHRs to levels similar to those of the WKY rats, 14 confirming a functional role for PI3K signaling pathway in this brain region unique to the SHR.In this study, we quantified the level of gene expression of specific class I PI3K subunits (p85␣, p85␤, p110␣, p110␤, p110␦, and p110␥) in the nucleus tractus solitarii (NTS) of SHRs relative to WKY rats using real-time RT-PCR and assessed any functional role of PI3K signaling in this structure for chronic regulation of arterial pressure. The NTS is the principal termination site of baroreceptor afferents 15,16 and, therefore, one of the key regulators of both ba...

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Section: Discussionmentioning

confidence: 92%

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

et al. 2009

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“…SHRs are widely used as an animal model to study the pathophysiology and management of hypertension, and a range of abnormalities have been reported in SHRs relative to the normal counterparts, including defection in both Akt-dependent and Akt-independent signaling pathways (Iaccarino et al, 2004 ; Hsiao et al, 2008 ), an increased vasoactive intestinal peptide-mRNA expression (Avidor et al, 1989 ), and a reduced content of vasopressin in the brain (Lang et al, 1981 ), among others, which are supposed to be either a causal or a compensatory factor for the hypertension on SHRs. As to the L-arginine/NO pathway in SHRs, the data varies, which probably depends on the age of the animals.…”

Section: Discussionmentioning

confidence: 99%

Rhynchophylline Ameliorates Endothelial Dysfunction via Src-PI3K/Akt-eNOS Cascade in the Cultured Intrarenal Arteries of Spontaneous Hypertensive Rats

et al. 2017

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Objectives: To examine the protective effect of Rhynchophylline (Rhy) on vascular endothelial function in spontaneous hypertensive rats (SHRs) and the underlying mechanism.Methods: Intrarenal arteries of SHRs and Wistar rats were suspended in myograph for force measurement. Expression and phosphorylation of endothelial nitric oxide (NO) synthase (eNOS), Akt, and Src kinase (Src) were examined by Western blotting. NO production was assayed by ELISA.Results: Rhy time- and concentration-dependently improved endothelium-dependent relaxation in the renal arteries from SHRs, but had no effect on endothelium-independent relaxation in SHR renal arteries. Wortmannin (an inhibitor of phosphatidylinositol 3-kinase) or PP2 (an inhibitor of Src) inhibited the improvement of relaxation in response to acetylcholine by 12 h-incubation with 300 μM Rhy. Western blot analysis revealed that Rhy elevated phosphorylations of eNOS, Akt, and Src in SHR renal arteries. Moreover, wortmannin reversed the increased phosphorylations of Akt and eNOS induced by Rhy, but did not affect the phosphorylation of Src. Furthermore, the enhanced phosphorylations of eNOS, Akt, and Src were blunted by PP2. Importantly, Rhy increased NO production and this effect was blocked by inhibition of Src or PI3K/Akt.Conclusion: The present study provides evidences for the first time that Rhy ameliorates endothelial dysfunction in SHRs through the activation of Src-PI3K/Akt-eNOS signaling pathway.

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“…29 In addition, the defective Akt-eNOS signaling in SHR causes the prehypertensive SHR to develop hypertension. 30 More recently, IGF-1/insulin can modify vascular responses via PI3K/NO pathways in the aorta of WKY rats, but the vascular effects of IGF-1/ insulin in the hypertensive SHRSP may be attenuated due to abnormalities in pathway regulation related to NO bioavailability. 7 Likewise, impaired IGF-1-Akt signaling, which decreases the total amount of PI3K in the heart, occurs at an early age and might contribute to the development of hypertension in SHRSP.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated Endothelial NOS Ser1177 via the PI3K/Akt Pathway Is Depressed in the Brain of Stroke-Prone Spontaneously Hypertensive Rat

Yoshitomi

Chen

Gao

et al. 2011

Journal of Stroke and Cerebrovascular Diseases

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Defective Phosphatidylinositol 3-Kinase Signaling in Central Control of Cardiovascular Effects in the Nucleus Tractus Solitarii of Spontaneously Hypertensive Rats

Cited by 10 publications

References 25 publications

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

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

Rhynchophylline Ameliorates Endothelial Dysfunction via Src-PI3K/Akt-eNOS Cascade in the Cultured Intrarenal Arteries of Spontaneous Hypertensive Rats

Phosphorylated Endothelial NOS Ser1177 via the PI3K/Akt Pathway Is Depressed in the Brain of Stroke-Prone Spontaneously Hypertensive Rat

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