Changes in elemental concentrations are associated with early stages of apoptosis in human monocyte-macrophages exposed to oxidized low-density lipoprotein: an X-ray microanalytical study

Skepper, Jeremy N.; Karydis, Ioannis; Garnett, Matthew; Hegyi, László; Hardwick, Simon J.; Warley, Alice; Mitchinson, M. J.; Cary, N.

doi:10.1002/(sici)1096-9896(199905)188:1<100::aid-path306>3.0.co;2-o

Cited by 39 publications

(25 citation statements)

References 32 publications

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“…What has separated sodium from potassium during apoptosis is the occurrence of an early increase in sodium during the cell death process. Several initial studies on ions and apoptosis have reported this early increase in intracellular sodium [85][86][87][88]. Additionally, we have shown that apoptotic cells have a significant increase in intracellular sodium that occurs prior to the dramatic loss of cell volume with a variety of apoptotic agents in Jurkat T-cells [89].…”

Section: Sodium As a Signal During Apoptosismentioning

confidence: 57%

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Bortner

Cidlowski

2007

Archives of Biochemistry and Biophysics

228

193

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The loss of cell volume or cell shrinkage has been a morphological hallmark of the programmed cell death process known as apoptosis. This isotonic loss of cell volume has recently been term apoptotic volume decrease or AVD to distinguish it from inherent volume regulatory responses that occurs in cells under anisotonic conditions. Recent studies examining the intracellular signaling pathways that result in this unique cellular characteristic have determined that a fundamental movement of ions, particularly monovalent ions, underlie the AVD process and plays an important role on controlling the cell death process. An efflux of intracellular potassium was shown to be a critical aspect of the AVD process, as preventing this ion loss could protect cells from apoptosis. However, potassium plays a complex role as a loss of intracellular potassium has also been shown to be beneficial to the health of the cell. Additionally, the mechanisms that a cell employs to achieve this loss of intracellular potassium vary depending on the cell type and stimulus used to induce apoptosis, suggesting multiple ways exist to accomplish the same goal of AVD. Additionally, sodium and chloride have been shown to play a vital role during cell death in both the signaling and control of AVD in various apoptotic model systems. This review examines the relationship between this morphological change and intracellular monovalent ions during apoptosis.

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Section: Sodium As a Signal During Apoptosismentioning

confidence: 57%

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Bortner

Cidlowski

2007

Archives of Biochemistry and Biophysics

228

193

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“…Another study with EPXMA reported similar elemental alterations in Na, Cl and K in association with DNA fragmentation detected by terminal transferase-mediated DNA nick-end labelling (TUNEL), a late molecular hallmark of apoptosis. 37 These microanalytical results have recently been confirmed in etoposide-induced apoptosis in prostate cancer cell lines. 38 However, in the LNCaP androgen-sensitive cell line, Cl content increased after androgen withdrawal and etoposide treatment.…”

Section: Discussionmentioning

confidence: 71%

Biphasic behavior of changes in elemental composition during staurosporine-induced apoptosis

et al. 2005

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Although the identification of events that occur during apoptosis is a fundamental goal of apoptotic cell death research, little is know about the precise sequence of changes in total elemental composition during apoptosis. We evaluated total elemental composition (Na, Mg, P, Cl, S, and K) in relation to molecular and morphological features in human U937 cells induced to undergo apoptosis with staurosporine, an intrinsic pathway activator. To evaluate total elemental content we used electron probe X-ray microanalysis to measure simultaneously all elements from single, individual cells. We observed two phases in the changes in elemental composition (mainly Na, Cl and K). The early phase was characterized by a decrease in intracellular K (P<0.001) and Cl (P<0.001) content concomitant with cell shrinkage, and preceded the increase in proteolytic activity associated with the activation of caspase-3. The later phase started with caspase-3 activation, and was characterized by a decrease in the K/Na ratio (P<0.001) as a consequence of a significant decrease in K and increase in Na content. The inversion of intracellular K and Na content was related with the inhibition of Na+/K+ ATPase. This later phase was also characterized by a significant increase (P<0.001) in intracellular Cl with respect to the early phase. In addition, we found a decrease in S content and an increase in the P/S ratio. These distinctive changes coincided with chromatin condensation and DNA fragmentation. Together, these findings support the concept that changes in total elemental composition take place in two phases related with molecular and morphological features during staurosporine-induced apoptosis.

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“…*P \ 0.05 compared to the control value measured at 1.5 h. # P \ 0.05 compared to the control value measured at 3 h content of intracellular K ? and Cl -take place during a time period as late as 2-48 h after apoptotic stimulation [39][40][41][42], but also as early as 15-60 min after the stimulation [43,44]. Thus, it appears that apoptosis is coupled to loss or efflux of cellular K ?…”

Section: Discussionmentioning

confidence: 99%

Early-phase occurrence of K+ and Cl− efflux in addition to Ca2+ mobilization is a prerequisite to apoptosis in HeLa cells

et al. 2012

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Sustained rise in cytosolic Ca(2+) and cell shrinkage mainly caused by K(+) and Cl(-) efflux are known to be prerequisites to apoptotic cell death. Here, we investigated how the efflux of K(+) and Cl(-) as well as the rise in cytosolic Ca(2+) occur prior to caspase activation and are coupled to each other in apoptotic human epithelial HeLa cells. Caspase-3 activation and DNA laddering induced by staurosporine were abolished by blockers of K(+) and Cl(-) channels or cytosolic Ca(2+) chelation. Staurosporine induced decreases in the intracellular free K(+) and Cl(-) concentrations ([K(+)](i) and [Cl(-)](i)) in an early stage prior to caspase-3 activation. Staurosporine also induced a long-lasting rise in the cytosolic free Ca(2+) concentration. The early-phase decreases in [K(+)](i) and [Cl(-)](i) were completely prevented by a blocker of K(+) or Cl(-) channel, but were not affected by cytosolic Ca(2+) chelation. By contrast, the Ca(2+) response was abolished by a blocker of K(+) or Cl(-) channel. Strong hypertonic stress promptly induced a cytosolic Ca(2+) increase lasting >50 min together with sustained shrinkage and thereafter caspase-3 activation after 4 h. The hypertonic stress induced slight increases in [K(+)](i) and [Cl(-)](i) in the first 50 min, but these increases were much less than the effect of shrinkage-induced condensation, indicating that K(+) and Cl(-) efflux took place. Hypertonicity induced caspase-3 activation that was prevented not only by cytosolic Ca(2+) chelation but also by K(+) and Cl(-) channel blockers. Thus, it is concluded that not only Ca(2+) mobilization but early-phase efflux of K(+) and Cl(-) are required for caspase activation, and Ca(2+) mobilization is a downstream and resultant event of cell shrinkage in both staurosporine- and hypertonicity-induced apoptosis.

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Changes in elemental concentrations are associated with early stages of apoptosis in human monocyte-macrophages exposed to oxidized low-density lipoprotein: an X-ray microanalytical study

Cited by 39 publications

References 32 publications

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Cell shrinkage and monovalent cation fluxes: Role in apoptosis

Biphasic behavior of changes in elemental composition during staurosporine-induced apoptosis

Early-phase occurrence of K+ and Cl− efflux in addition to Ca2+ mobilization is a prerequisite to apoptosis in HeLa cells

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