Activation of AMP-activated Protein Kinase α1 Alleviates Endothelial Cell Apoptosis by Increasing the Expression of Anti-apoptotic Proteins Bcl-2 and Survivin

Abstract

Accumulating evidence suggests that AMP-activated protein kinase (AMPK) activation exerts anti-apoptotic effects in multiple types of cells. However, the underlying mechanisms remain poorly defined. The aim of the present study was to determine how AMPK suppresses apoptosis in endothelial cells exposed to hypoxia and glucose deprivation (OGD). AMPK activity, NF-B activation, and endothelial cell apoptosis were assayed in cultured endothelial cells and mouse common carotid artery with or without OGD treatment. OGD markedly activated AMPK as early as 30 min, and AMPK activity reached maximal at 2 h of OGD. Endothelial apoptosis was not detected until 2 h of OGD but became markedly elevated at 6 h of OGD treatment. Furthermore, AMPK inhibition by Compound C or overexpression of dominant negative AMPK (AMPK-DN) exacerbated, whereas AMPK activation by pharmacologic (aminoimidazole carboxamide ribonucleotide (AICAR)) or genetic means (overexpression of constitutively active AMPK) suppressed endothelial cell apoptosis caused by OGD. Concomitantly, AMPK activation increased the expression of both Bcl-2 and Survivin, two potent anti-apoptotic proteins. Furthermore, AMPK activation significantly enhanced IB␣ kinase activation, NF-B nuclear translocation, and DNA binding activity of NF-B. Consistently, selective inhibition of NF-B, which abolished OGD-enhanced expression of Bcl-2 and Survivin, accentuated endothelial apoptosis caused by OGD. Finally, we found that genetic deletion of the AMPK␣1, but not AMPK␣2, suppressed OGD-enhanced NF-B activation, the expression of Bcl-2 and Survivin, and endothelial apoptosis. Overall, our results suggest that AMPK␣1, but not AMPK␣2 activation, promotes cell survival by increasing NF-B-mediated expression of anti-apoptotic proteins (Bcl-2 and Survivin) and intracellular ATP contents.

Shear stress-induced mitochondrial biogenesis decreases the release of microparticles from endothelial cells

“…Under exercise, activated AMPK increases the level of intracellular NAD ϩ and induces further enhancement of NAD ϩ -dependent deacetylase SIRT1 (19). Activation of AMPK is known to alleviate apoptosis in vascular ECs (25,28). Together, the crosstalk in the pathway between SIRT1 and AMPK can be another possible mechanism for the reduction of endothelial activation/apoptosis under aerobic exercise.…”

AMPK Potentiates Hypertonicity-induced Apoptosis by Suppressing NFκB/COX-2 in Medullary Interstitial Cells

“…Liu et al 45 demonstrated that activation of AMPK␣1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin. However, the study by Zhang et al 46 showed that activation of AMPK contributes to apoptosis in glioblastoma cells via p53 activation and mTORC1 inhibition.…”

Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 Mediates STIM1 Protein Phosphorylation to Inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38β Mitogen-activated Protein Kinase

“…Because endothelial cells express both the catalytic ␣1-and ␣2-subunits of AMPK (25)(26)(27)(28), we compared the extent of phosphorylation of the ␣1-and ␣2-subunits in response to thrombin. We observed that thrombin induced phosphorylation of the ␣1-subunit but not the ␣2-subunit of AMPK in HLMVECs.…”

“…Endothelial cells express both ␣1 and ␣2 subunits (25)(26)(27)(28). The above results showed that pharmacological activation of AMPK induced STIM1 phosphorylation and suppressed SOCE, so we addressed which isoform of the ␣-subunits of AMPK were involved in regulating SOCE in HLMVECs.…”