Cytosolic pH regulation in mouse macrophages. Proton extrusion by plasma-membrane-localized H+-ATPase

Tapper, Hans; Sundler, Roger

doi:10.1042/bj2810245

Cited by 46 publications

(36 citation statements)

References 28 publications

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“…1). Although S-SMaseinduced LDL aggregation under these conditions may be relevant in more advanced lesions, where an acidic environment may exist in the vicinity of lesion macrophages (27,28) or as a result of hypoxia-induced metabolic acidosis (57), early lipoprotein aggregation likely occurs at a more neutral, physiologic pH. Thus, our finding that certain types of atherogenic lipoproteins are substrates for S-SMase at neutral pH may have relevance to early atherogenesis.…”

Section: Discussionmentioning

confidence: 84%

Secretory Sphingomyelinase, a Product of the Acid Sphingomyelinase Gene, Can Hydrolyze Atherogenic Lipoproteins at Neutral pH

Schissel¹,

Jiang²,

Tweedie-Hardman³

et al. 1998

Journal of Biological Chemistry

305

263

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The subendothelial aggregation and retention of low density lipoprotein (LDL) are key events in atherogenesis, but the mechanisms in vivo are not known. Previous studies have shown that treatment of LDL with bacterial sphingomyelinase (SMase) in vitro leads to the formation of lesion-like LDL aggregates that become retained on extracellular matrix and stimulate macrophage foam cell formation. In addition, aggregated human lesional LDL, but not unaggregated lesional LDL or plasma LDL, shows evidence of hydrolysis by an arterial wall SMase in vivo, and several arterial wall cell types secrete a SMase (S-SMase). S-SMase, however, has a sharp acid pH optimum using a standard in vitro SMmicelle assay. Thus, a critical issue regarding the potential role of S-SMase in atherogenesis is whether the enzyme can hydrolyze lipoprotein-SM, particularly at neutral pH. We now show that S-SMase can hydrolyze and aggregate native plasma LDL at pH 5.5 but not at pH 7.4. Remarkably, LDL modified by oxidation, treatment with phospholipase A 2 , or enrichment with apolipoprotein CIII, which are modifications associated with increased atherogenesis, is hydrolyzed readily by S-SMase at pH 7.4. In addition, lipoproteins from the plasma of apolipoprotein E knock-out mice, which develop extensive atherosclerosis, are highly susceptible to hydrolysis and aggregation by S-SMase at pH 7.4; a high SM:PC ratio in these lipoproteins appears to be an important factor in their susceptibility to S-SMase. Most importantly, LDL extracted from human atherosclerotic lesions, which is enriched in sphingomyelin compared with plasma LDL, is hydrolyzed by S-SMase at pH 7.4 10-fold more than same donor plasma LDL, suggesting that LDL is modified in the arterial wall to increase its susceptibility to S-SMase. In summary, atherogenic lipoproteins are excellent substrates for S-SMase, even at neutral pH, making this enzyme a leading candidate for the arterial wall SMase that hydrolyzes LDL-SM and causes subendothelial LDL aggregation.

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Section: Discussionmentioning

confidence: 84%

Secretory Sphingomyelinase, a Product of the Acid Sphingomyelinase Gene, Can Hydrolyze Atherogenic Lipoproteins at Neutral pH

Schissel¹,

Jiang²,

Tweedie-Hardman³

et al. 1998

Journal of Biological Chemistry

305

263

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“…Bafilomycin (1 pM, 10 min), demonstrated to inhibit cytoplasm alkalinization after artificial acidification [12,13], was ineffective in our experiments (Table 1). Earlier it was reported to be of no effect on the pHi in adherent macrophages [9]. Whether H+-ATPase in these cells was resistant to bafilomycin, or NEM and CI-NBD have some other mechanism of action remains to be studied.…”

Section: Resultsmentioning

confidence: 99%

“…We have checked whether the inhibition of H+-ATPase affects cell density-dependent modulation of the pHi. Plasma membrane-localized H+-ATPase was found to be operative at physiological pH~ levels and to contribute to the maintenance of a steady-state pH~ in adherent resident macrophages [8,9] and osteoclasts [10]. We have treated cell cultures with the H+-ATPase inhibitors [11] C1-NBD, NEM and bafilomycin (the latter reported to be a specific inhibitor of vacuolar type H ÷-ATPase).…”

Section: Resultsmentioning

confidence: 99%

Regulation of intracellular pH by cell‐cell adhesive interactions

et al. 1995

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As was shown in our previous work, the intracellular pH (pHi) of cultured human fibroblasts depends on cell density. The pH i is lOW in single cells, higher in cells, forming small groups and maximal in a sparse monolayer. On the other hand, the pH~ is low in areas of confluent monolayers. In the present work, we show that the effects of inhibitors of various pH-controlling mechanisms as well as inhibitors of key enzymes in signal transduction pathways depend on the local cell density. We have found that N-ethylmaleimide and 7-chloro-4-nitrobenz-2-oxa-l,3-diazole, known as inhibitors of V-type H ÷ ATPase, inhibit the elevation of pHi induced by cell-cell contact interactions; meanwhile Cd 2+ ions, which inhibit H ÷ conductive pathway, cause an increase of pHi in a confluent monolayer. Our data revealed also that the Na+/H + antiporter does not play an essential role in the pH~ regulation by intercellular contacts.Inhihitors of phospholipase A2 (4-bromophenacyl-bromide), phospholipase C (neomycin) and protein kinase C (H-7) dramatically change the way the pH i is modulated by local cell density. It is suggested that cell-cell interactions regulate cell activities via modulation of pHi, which is under positive control from phospholipase A2 and under negative control from protein kinase C.

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“…In vivo and in vitro results suggest that lysosomal enzymes, including pCD, are released from monocyte-derived macrophages in atherosclerotis lesions [32,155]. Macrophages are able to acidify their environment by proton pumps and secretion of lactic acid [156,157]. Therefore, macrophage pericellular environment may be sufficiently acidic for CD activation.…”

Section: Atherosclerosismentioning

confidence: 95%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

540

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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Cytosolic pH regulation in mouse macrophages. Proton extrusion by plasma-membrane-localized H+-ATPase

Cited by 46 publications

References 28 publications

Secretory Sphingomyelinase, a Product of the Acid Sphingomyelinase Gene, Can Hydrolyze Atherogenic Lipoproteins at Neutral pH

Secretory Sphingomyelinase, a Product of the Acid Sphingomyelinase Gene, Can Hydrolyze Atherogenic Lipoproteins at Neutral pH

Regulation of intracellular pH by cell‐cell adhesive interactions

Cathepsin D—Many functions of one aspartic protease

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