Lipopolysaccharide induces endothelial cell apoptosis via activation of Na+/H+ exchanger 1 and calpain-dependent degradation of Bcl-2

The calcium-dependent protease calpain is involved in lipopolysaccharide (LPS)-induced endothelial injury. The activation of Na+/H+ exchanger (NHE) is responsible to increase intracellular Ca2+ (Cai2+) in cardiovascular diseases. Here we hypothesized that activation of NHE mediates LPS-induced endothelial cell apoptosis via calcium-dependent calpain pathway. Our results revealed that LPS-induced increases in NHE activity are dependent on NHE1 in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with LPS increased the NHE1 activity in a time-dependent manner associated with the increased Cai2+, which resulted in enhanced calpain activity as well as HUVECs apoptosis via NHE1-dependent degradation of Bcl-2.

The current study demonstrates that LPS induces vascular endothelial cell apoptosis by triggering calpain-dependent degradation of Bcl-2 via activating NHE1. Inhibition of NHE1 reverses LPS-induced increase of calcium concentration and calpain activity. In addition, inhibition of NHE1 by cariporide or RNA interference blocked the decrease of Bcl-2 degradation caused by LPS. These results strongly suggest that NHE1 is required for LPS-induced endothelial cell apoptosis via calcium-dependent protease calpain.Figure optionsDownload as PowerPoint slideHighlights
► LPS-induced increases in NHE activity are dependent on NHE1 in HUVECs.
► LPS increases intracellular calcium level via activation of NHE1.
► LPS-enhanced calpain activity is both NHE1 and calcium-dependent.
► LPS induces NHE1 activation-dependent Bcl-2 degradation.
► NHE1 activation is required for LPS-induced HUVECs apoptosis.