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Amiloride derivatives induce apoptosis by depleting ER Ca(2+) stores in vascular endothelial cells Park KS; Poburko D; Wollheim CB; Demaurex NBr J Pharmacol 2009[Apr]; 156 (8): 1296-304BACKGROUND AND PURPOSE: Amiloride derivatives are blockers of the Na(+)/H(+) exchanger (NHE) and at micromolar concentrations have protective effects on cardiac and brain ischaemia/reperfusion injury but at higher concentrations also induce apoptosis. Here, we aimed to elucidate the mechanism related to this cytotoxic action. EXPERIMENTAL APPROACH: We quantified the expression of genes associated with endoplasmic reticulum (ER) stress and measured changes in luminal ER Ca(2+) concentration ([Ca(2+)](ER)) with a 'cameleon' indicator, D1ER. KEY RESULTS: Amiloride derivatives induced apoptosis in vascular endothelial cells, an effect that increased at alkaline extracellular pH. The potency order for cytotoxicity was 5-(N,N-hexamethylene)-amiloride (HMA) > 5-(N-methyl-N-isobutyl) amiloride > 5-(N-ethyl-N-isopropyl) amiloride (EIPA) >> amiloride. HMA dose-dependently increased the transcription of the ER stress genes GADD153 and GADD34 and rapidly depleted [Ca(2+)](ER), mimicking the effects of the sarco/endoplasmic reticulum ATPase (SERCA) inhibitor thapsigargin. The NHE1-specific inhibitor HOE 694 inhibited NHE activity by 87% but did not alter [Ca(2+)](ER). The decrease in [Ca(2+)](ER) evoked by amiloride derivatives was also observed in HeLa cells and was mirrored by an increase in cytosolic Ca(2+) concentration. CONCLUSIONS AND IMPLICATIONS: Amiloride derivatives disrupt ER and cytosolic Ca(2+) homeostasis by a mechanism unrelated to NHE inhibition, most likely by interfering with the activity of SERCA. We propose that ER Ca(2+) depletion and subsequent ER stress provide a rationale framework for the apoptotic effects of amiloride derivatives.|Amiloride/analogs & derivatives/*toxicity[MESH]|Antigens, Differentiation/genetics[MESH]|Apoptosis/*drug effects[MESH]|Calcium/*metabolism[MESH]|Cell Cycle Proteins/genetics[MESH]|Diuretics/*toxicity[MESH]|Dose-Response Relationship, Drug[MESH]|Endoplasmic Reticulum/*drug effects/metabolism[MESH]|Endothelial Cells/*drug effects/metabolism/pathology[MESH]|Enzyme Inhibitors/pharmacology[MESH]|Guanidines/pharmacology[MESH]|HeLa Cells[MESH]|Humans[MESH]|Hydrogen-Ion Concentration[MESH]|Kinetics[MESH]|Protein Phosphatase 1[MESH]|Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism[MESH]|Sodium-Hydrogen Exchangers/antagonists & inhibitors/metabolism[MESH]|Sulfones/pharmacology[MESH]|Thapsigargin/pharmacology[MESH]|Transcription Factor CHOP/genetics[MESH]|Transcription, Genetic/drug effects[MESH] |
