Classical isoforms of PKC as regulators of CAT-1 transporter activity in pulmonary artery endothelial cells

Krotova, Karina; Zharikov, Sergey; Block, Edward R.

doi:10.1152/ajplung.00308.2002

Cited by 46 publications

(47 citation statements)

References 40 publications

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“…A previous study indicated that melatonin decreases PKC activity in glioma cells (17), which was supported by our data showing the possible role of melatonin as a PKC inhibitor. In addition, our data are in agreement with a previous report showing that PKC-α regulates CAT-1 transport activity independent of its expression (13).…”

Section: Melatonin Regulates Pkc In Bdl Ratssupporting

confidence: 93%

“…It seems possible that melatonin reduces consumption of l-arginine via arginase II to increase renal l-arginine levels. Because different cell types express different members of the PKC and CAT families for the delivery of l-arginine (13,18), further study is needed to elucidate whether the protective role of melatonin on the l-arginine pathway might be due to its regulation of other PKC isoforms. Dashed lines indicate the effects of melatonin on BDL rats: melatonin inhibits protein kinase C-α (PKC-α) activity, consequently amplifying CAT-1-mediated l-arginine uptake and decreasing NADPH oxidase in the BDL liver; melatonin inhibits PKC-β activity to reduce NADPH oxidase-derived superoxide production in the BDL kidney; and melatonin reduces arginase II to increase l-arginine levels in the BDL kidney.…”

Section: Melatonin Regulates Pkc In Bdl Ratsmentioning

confidence: 99%

“…PKC is a superfamily of serine-threonine kinases and incorporates 12 isoforms, including conventional PKC isoforms (α, βI, βII, γ). Several contributions have investigated the role of conventional PKC in the regulation of l-arginine metabolism, although with contradicting results (10)(11)(12)(13)). Yet most of these studies suggest that activation of PKC-α inhibits CAT-1 for the delivery of l-arginine.…”

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confidence: 99%

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Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: role of protein kinase C

et al. 2013

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Background: Bile duct ligation (BDL) is a commonly used cholestatic liver disease (cLD) model. We recently found that l-arginine levels were significantly raised by melatonin in young rats with BDL. We hypothesized that protein kinase c-α (PKc-α) is involved in the increases of l-arginine in melatonintreated BDL rats. In addition, we tested whether melatonin prevents nicotinamide adenine dinucleotide phosphate (NADPh) oxidase-induced reactive oxygen species (ROs) production, in rats with BDL, through PKc. Methods: Four groups of young male rats were studied: shams (n = 6), untreated BDL rats (n = 9), melatonin-treated shams (n = 6, M), and melatonin-treated BDL rats (n = 6, BDL + M). Melatonin-treated rats received daily melatonin 1 mg/kg/d via i.p. injection. All surviving rats were killed 14 d after surgery. results: Melatonin prevented BDL-induced mortality and kidney injury. Melatonin additionally increased l-arginine concentrations in BDL liver, which is correlated with decreased PKc-α translocation. Next, melatonin increased l-arginine levels in BDL kidneys, which was correlated with decreased renal levels of arginase II. In the BDL kidney, melatonin decreased PKc-β translocation, reduced p47phox translocation, and diminished NADPh-dependent superoxide production. conclusion: Melatonin inhibits PKc-α to increase cationic amino acid transporter-1 (cAT-1)-mediated l-arginine uptake in BDL liver, whereas it inhibits PKc-β to reduce NADPhdependent superoxide production.

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Section: Melatonin Regulates Pkc In Bdl Ratssupporting

confidence: 93%

Section: Melatonin Regulates Pkc In Bdl Ratsmentioning

confidence: 99%

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confidence: 99%

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Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: role of protein kinase C

et al. 2013

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“…CRF binding to CRFR1 can induce PKC signaling, but at least 12 isoforms of PKC have been described (47,48). We found that PKC-e, but not PKC-βII or PKC-γ, is up-regulated in cultured primary astrocytes after CRF challenge (Fig.…”

Section: Discussionmentioning

confidence: 69%

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

Chen

Yang

Kong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: (i) both CRFR1 and AQP4 are expressed; (ii) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca 2+, and PKCe; and (iii) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1+ and AQP4 + , we show that transfected CRFR1+ contributes to edema via transfected AQP4 + . In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema.water permeability | high altitude | acute mountain sickness A pproximately 140 million people around the world live at altitudes of >2,500 m, including >8 million who live on the Qinghai-Tibet plateau of China at an average elevation of >4,000 m. Living at these altitudes requires physiological adaptations to compensate for the lower partial pressure of oxygen (1). In travelers who ascend to altitudes too high or too quickly (2-4) or in people with fatigue and infection or psychological stress (3, 4), hypoxia can induce acute mountain sickness (AMS) that can develop into high-altitude cerebral edema (HACE), a serious and often fatal condition (2-6). Today's ability to travel rapidly to high altitudes means that, every year, millions of people are exposed to the risk of AMS and HACE (7).In human volunteers exposed for 32 h to hypobaric hypoxia (corresponding to 4,572 m altitude), brain volume increases by 2.77% (8), whereas normobaric hypoxia (12% O 2 , corresponding to a simulated altitude of 4,500 m) for 16 h produces 50% AMS, headache, a mild increase in brain volume, and cytotoxic cerebral edema (9). A recent study reported that seven of nine male students exposed to isobaric hypoxia (inhaled room air enriched with N 2 for 6 h to obtain arterial saturation values of 75-80%) developed AMS; the mean apparent diffusion coefficient (ADC) increased by 2.12% in these subjects, indicating mild extracellular (vasogenic) cerebral edema. The ADC changes were negatively correlated with AMS scores, suggesting that severe AMS is associated with intracellular (cytotoxic) cerebral edema in addition to vasogenic edema (10).In parallel with the increasing brain water content, hypoxia acutely activates the hypothalamic-pituitary-adrenal axis in rats (11-13), increasing corticotropin-releasing factor (CRF) and endothelin-1 (ET-1)...

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“…In a similar manner, it has been reported that ␣, ␤-unsaturated aldehydes, which are abundantly present in CSE, are highly reactive toward thiols, directly forming sulfhydryl-ether linkages. 32 Alternatively, protein kinase C-mediated modification of arginine transport has been demonstrated previously, 33 and CSE has been shown to activate protein kinase C in non-ECs. 34 However, we did not observe any diminution of the effects of CSE on arginine transport during coincubation with the protein kinase C inhibitor BIM-I (data not shown).…”

Section: Discussionmentioning

confidence: 87%

Adverse Effects of Cigarette Smoke on NO Bioavailability

et al. 2006

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Abstract-Endothelial dysfunction is a hallmark of cardiovascular disease, and the L-arginine:NO pathway plays a critical role in determining endothelial function. Recent studies suggest that smoking, a well-recognized risk factor for vascular disease, may interfere with L-arginine and NO metabolism; however, this remains poorly characterized. Accordingly, we performed a series of complementary in vivo and in vitro studies to elucidate the mechanism by which cigarette smoke adversely affects endothelial function. In current smokers, plasma levels of asymmetrical dimethyl-arginine (ADMA) were 80% higher (Pϭ0.01) than nonsmokers, whereas citrulline (17%; PϽ0.05) and N-hydroxy-L-arginine (34%; PϽ0.05) were significantly lower. Exposure to 10% cigarette smoke extract (CSE) significantly affected endothelial arginine metabolism with reductions in the intracellular content of citrulline (81%), N-hydroxy-L-arginine (57%), and arginine (23%), while increasing ADMA (129%). CSE significantly inhibited (38%) arginine uptake in conjunction with a 34% reduction in expression of the arginine transporter, CAT1. In conjunction with these studies, CSE significantly reduced the activity of eNOS and NO production by endothelial cells, while stimulating the production of reactive oxygen species. In conclusion, cigarette smoke adversely affects the endothelial L-arginine NO synthase pathway, resulting in reducing NO production and elevated oxidative stress. In conjunction, exposure to cigarette smoke increases ADMA concentration, the latter being a risk factor for cardiovascular disease. Key Words: smoking Ⅲ endothelium Ⅲ metabolism A therosclerotic coronary and cerebrovascular disease are leading causes of death and disability in the Western world, and cigarette smoking has been clearly identified as a risk factor for coronary artery disease (reviewed by Ambrose and Barua 1 ). In this context, measures of endothelial function have been associated with cardiovascular outcome, 2 and smoking has been widely associated with reduced endothelial function. 3 The endothelium plays a central role in the modulation of vascular tone, the inhibition of platelet aggregation and vascular smooth muscle proliferation, and a key participation in angiogenesis under appropriate conditions. NO is well recognized as playing a pivotal part in these endothelial properties, being produced by the endothelial isoform of NO from its preferred substrate L-arginine. In this context, provision of sufficient L-arginine is critical for the sustained production of NO supply, 4 mediated in endothelial cells (ECs) principally by the type 1 cationic amino acid transporter (CAT1). Previous studies indicate that deleterious actions of cigarette smoke on endothelial function could be mitigated by supplemental L-arginine; 5 however, to date, the precise basis for this interaction remains unclear. One explanation is that cigarette smoke exerts an inhibitory effect on components of the L-arginine:NO pathway to influence NO production. In addition, potential effects of cigar...

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Classical isoforms of PKC as regulators of CAT-1 transporter activity in pulmonary artery endothelial cells

Abstract: Krotova, Karina Y., Sergey I. Zharikov, and Edward R. Block. Classical isoforms of PKC as regulators of CAT-1 transporter activity in pulmonary artery endothelial cells.

Cited by 46 publications

References 40 publications

Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: role of protein kinase C

Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: role of protein kinase C

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

Adverse Effects of Cigarette Smoke on NO Bioavailability

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