Activation of AMP-activated protein kinase by metformin protects human coronary artery endothelial cells against diabetic lipoapoptosis.
BACKGROUND
The prevalence of type 2 diabetes (T2D) among adults worldwide is rapidly increasing, and in patients with diabetes the major cause of death is macrovascular disease. Endothelial cells play an important role in maintaining vascular homeostasis. Free fatty acids, which are elevated in T2D, have previously been shown to induce endothelial dysfunction and apoptosis of endothelial cells, which is considered as an important and early factor in the onset of atherosclerosis and cardiovascular disease. Metformin, which is used as first line treatment of T2D patients, is believed to exert its pharmacological effects through activation of AMP-activated protein kinase, which has emerged as a new potential target in reversing endothelial dysfunction.


METHODS
Here we studied the protective effect of metformin against free fatty acid-induced apoptosis of human coronary artery endothelial cells (HCAECs) by assessing DNA fragmentation and cleaved caspase 3 levels. We also attempted to elucidate the underlying mechanisms by investigating the involvement of AMP-activated protein kinase, p38 MAPK and eNOS. Generation of reactive oxygen species by free fatty acid exposure was also examined.


RESULTS
Our results suggest that metformin protects HCAECs from lipoapoptosis, an effect that involves eNOS and p38 MAPK, downstream of AMPK signaling, but not as previously suggested through suppression of reactive oxygen species.


CONCLUSIONS
The protective effect of metformin against free fatty acid induced apoptosis is potentially clinically relevant as metformin is first line treatment for patients with T2D, a patient group which is rapidly increasing and carries a high burden of cardiovascular disease.
Department of Clinical Science and Education, Section of Endocrinology and Diabetology, Karolinska Institutet, Södersjukhuset AB, Stockholm, Sweden. linnea.eriksson@ki.se.|Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden. linnea.eriksson@ki.se.
Linnéa
L
Eriksson
Department of Clinical Science and Education, Section of Endocrinology and Diabetology, Karolinska Institutet, Södersjukhuset AB, Stockholm, Sweden. thomas.nystrom@ki.se.
Thomas
T
Nyström
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D007004:Hypoglycemic Agents; D017382:Reactive Oxygen Species; D008687:Metformin; D055372:AMP-Activated Protein Kinases