Altered signal pathway in angiotensin II-stimulated neutrophils of patients with hypercholesterolaemia

Paragh, György; Szabó, J; Kovács, Éva; Keresztes, T.; Kárpáti, István; Balogh, Zoltán; Páll, Dénes; Fóris, Gabriella

doi:10.1016/s0898-6568(02)00017-7

Cited by 29 publications

(28 citation statements)

References 25 publications

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“…[5][6][7][8] It should be pointed out that the level of IP 3 , [Ca 2þ ]i, and membrane-bound PKC activity in resting monocytes are in reasonable agreement with those already found both in the literature and our earlier work. [10][11][12] In our present study, LDL induced the IP3 and Ca 2þ signals and PKC activation and translocation into the membrane in human monocytes. The PKC activation in the membrane fraction was inhibited by PT and H-7, suggesting that PKC activation depends on the IP 3 and Ca 2þ signal.…”

Section: Discussionsupporting

confidence: 54%

“…9 In our earlier publications, it was demonstrated that neutrophils of patients with hypercholesterolemia are characterized by increased membrane-bound PKC activity and by decreased signal processing through chemotactic peptide receptors such as FMLP and angiotensin II. [10][11][12] Consequently, if it is true that LDL-Rs have a dual signaling system, and this system is involved in the regulation of intracellular cholesterol homeostasis, then clarification of LDL-R signaling may produce very significant data to help the better understanding of the pathomechanism of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

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Crosstalk of sterol‐dependent and non‐sterol‐dependent signaling in human monocytes after in vitro addition of LDL

Serés

Fóris

Kovács

et al. 2006

Cell Biochemistry & Function

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The aim of the present study was to investigate low density lipoprotein (LDL)-induced, non-sterol-dependent signaling and its possible role in cholesterol balance. LDL in 10 microg ml(-1) concentration could induce inositol trisphosphate (IP3) and Ca2+ signal generation through a pertussis toxin (PT) sensitive G protein in human monocytes. The increase in [Ca2+]i was derived from the intracellular pools. LDL also induced activation and translocation of protein kinase C (PKC) into the cell membrane, by processes, which were significantly inhibited in the first 20 min by preincubation with PT and PKC-inhibitor H-7. The PKC-activating phorbol-12-myristate-13-acetate (PMA), differently from LDL, enhanced the LDL-receptor (LDL-R)-mediated binding and degradation of [125I]LDL, but inhibited endogenous cholesterol synthesis, and both effects were inhibited by H-7. The LDL-induced inhibition of binding and degradation of [125I]LDL was not affected by H-7, whereas decreased cholesterol synthesis was counteracted by H-7. These results suggest the existence of a non-sterol-dependent signal pathway of LDL-Rs, by which endogenous cholesterol synthesis, that is, the [14C]acetate incorporation, is regulated through PKC activation.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Crosstalk of sterol‐dependent and non‐sterol‐dependent signaling in human monocytes after in vitro addition of LDL

Serés

Fóris

Kovács

et al. 2006

Cell Biochemistry & Function

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“…58,59 If this holds true, it is possible that certain patients who likely are quite advanced along the clinical continuum that starts with tendency toward mild weight gain and dieting, and moves toward obesity and metabolic syndrome have enough excess cholesterol in their cell membranes to interfere with the CCK satiety servomechanism (Figure 1). It is possible that these patients will need a 'corrective PAM' without intrinsic agonist activity, representing a second drug, to complement the PAMs without intrinsic agonist activity that act at the normal receptor in a normal membrane environment.…”

Section: Membrane Cholesterol Composition In Obesitymentioning

confidence: 99%

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

et al. 2016

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The gastrointestinal (GI) tract has a central role in nutritional homeostasis, as location for food ingestion, digestion and absorption, with the gut endocrine system responding to and regulating these events, as well as influencing appetite. One key GI hormone with the full spectrum of these activities is cholecystokinin (CCK), a peptide released from neuroendocrine I cells scattered through the proximal intestine in response to fat and protein, with effects to stimulate gall bladder contraction and pancreatic exocrine secretion, to regulate gastric emptying and intestinal transit, and to induce satiety. There has been interest in targeting the type 1 CCK receptor (CCK1R) for drug development to provide non-caloric satiation as an aid to dieting and weight loss; however, there have been concerns about CCK1R agonists related to side effects and potential trophic impact on the pancreas. A positive allosteric modulator (PAM) of CCK action at this receptor without intrinsic agonist activity could provide a safer and more effective approach to long-term administration. In addition, CCK1R stimulus-activity coupling has been shown to be negatively affected by excess membrane cholesterol, a condition described in the metabolic syndrome, thereby potentially interfering with an important servomechanism regulating appetite. A PAM targeting this receptor could also potentially correct the negative impact of cholesterol on CCK1R function. We will review the molecular basis for binding natural peptide agonist, binding and action of small molecules within the allosteric pocket, and the impact of cholesterol. Novel strategies for taking advantage of this receptor for the prevention and management of obesity will be reviewed.International Journal of Obesity Supplements (2016) 6, S22-S27; doi:10.1038/ijosup.2016.5 INTRODUCTIONThe prevalence of obesity has been progressively increasing throughout the United States and around the world, contributing to a parallel increase in the prevalence of type 2 diabetes mellitus and its associated comorbidities. 1 These problems have been responsible for extraordinary morbidity, suffering, loss in productivity and premature mortality. In spite of major efforts to develop effective weight reduction diets, diet aids, medications, medical devices and surgical procedures, the trajectory for this continues in the wrong direction. Bariatric surgery has proven to be quite effective in patients with morbid obesity; 2 however, this is quite expensive and not scalable, certainly not keeping up with the increasing prevalence of the most severe end of this clinical continuum. The activity of acute dieting and exercise has been similarly effective in inducing weight loss; however, it has not been durable, with an extremely high incidence of regaining weight to or even beyond the starting point. After a long hiatus in approved drugs, three new diet medications have recently been approved, 3-5 but all carry concerns about safety, and there are requirements for registration and careful clinical follow-up, re...

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“…Consequently, cells located in the atherosclerotic lesions are exposed to an FC-rich extracellular environment. Extracellular FC can be directly incorporated into the plasma membranes (PMs) of cells, leading to an increase in cellular cholesterol levels (6,7). Indeed, Fang et al (8) showed that hypercholesterolemia increased the level of cellular FC ϳ2-4-fold in vascular endothelial cells (ECs).…”

Section: Vascular Endothelial Function Is Impaired In Hypercholesteromentioning

confidence: 99%

Angiotensin II Impairs Endothelial Nitric-oxide Synthase Bioavailability under Free Cholesterol-enriched Conditions via Intracellular Free Cholesterol-rich Membrane Microdomains

Amiya

Watanabe

Takeda

et al. 2013

Journal of Biological Chemistry

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Background: Free cholesterol forms membrane microdomains in endothelial cells. Results: Free cholesterol loading formed intracellular vesicles with free cholesterol-rich microdomains that were shifted toward late endosomes/lysosomes by angiotensin II, resulting in impairment of endothelial NOS availability. Conclusion: Angiotensin II decreased the bioavailability of endothelial NOS in a free cholesterol-enriched condition. Significance: Free cholesterol-rich microdomains are crucial platforms of endothelial NOS availability.

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Altered signal pathway in angiotensin II-stimulated neutrophils of patients with hypercholesterolaemia

Cited by 29 publications

References 25 publications

Crosstalk of sterol‐dependent and non‐sterol‐dependent signaling in human monocytes after in vitro addition of LDL

Crosstalk of sterol‐dependent and non‐sterol‐dependent signaling in human monocytes after in vitro addition of LDL

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

Angiotensin II Impairs Endothelial Nitric-oxide Synthase Bioavailability under Free Cholesterol-enriched Conditions via Intracellular Free Cholesterol-rich Membrane Microdomains

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