AMP‐activated protein kinase activation inhibits human endothelial cell proliferation

Abstract

AMP‐activated protein kinase (AMPK) is a ubiquitously distributed energy sensing enzyme that is activated by changes in cellular metabolism. Recent studies indicate that AMPK influences endothelial cell (EC) function and vascular homeostasis, but the underlying mechanisms are not fully known. In the present study, we investigated whether AMPK regulates EC proliferation. Treatment of cultured human umbilical vein ECs with serum stimulated a time‐dependent increase in cell number that was inhibited by the AMPK activators, 5‐aminoimidazole‐4‐carboxamide‐1‐â‐D‐ribofuranoside (AICAR), A‐769662, and metformin. The anti‐proliferative action of AICAR was concentration‐dependent, reversed by the adenosine kinase inhibitor 5’‐iodotubercidin, but unaffected by the nitric oxide synthase inhibitor, methyl‐L‐arginine. Infection of ECs with an adenovirus expressing constitutively active AMPKα also blocked EC proliferation. In addition, AMPK activation resulted in a marked decline in DNA synthesis that was associated with the arrest of ECs in the G0/G1 phase of the cell cycle. In conclusion, this study demonstrates that AMPK activation inhibits serum‐stimulated EC proliferation by blocking cell cycle progression. The ability of AMPK to inhibit EC growth may provide another mechanism by which this kinase preserves cellular energy during periods of metabolic stress. Supported by NIH grant HL59976.