Mitochondrial dysfunction enhances the migration of vascular smooth muscles cells via suppression of Akt phosphorylation.
BACKGROUND
Atherosclerosis is one of the major complications of diabetes, which may result from insulin resistance via mitochondrial dysfunction. Although a strong association between insulin resistance and cardiovascular disease has been suggested, it is not clear yet whether stress-inducing factors damage mitochondria and insulin signaling pathway in cardiovascular tissues.


METHODS
We investigated whether stress-induced mitochondrial dysfunction might alter the insulin/Akt signaling pathway in A10 rat vascular smooth muscle cells (VSMC).


RESULTS
The treatment of oxidized low density lipoprotein (oxLDL) decreased ATP contents, mitochondrial respiration activity, mRNA expressions of OXPHOS subunits and IRS-1/2 and insulin-mediated phosphorylations of Akt and AMP-activated protein kinase (AMPK). Similarly, dideoxycytidine (ddC), the mtDNA replication inhibitor, or rotenone, OXPHOS complex I inhibitor, inhibited the insulin-mediated pAkt while increased pAMPK regardless of insulin. Reciprocally, an inhibitor of Akt, triciribine (TCN), decreased cellular ATP contents. Overexpression of Akt dominant positive reversed the oxLDL- or ddC-mediated ATP decrease but AMPK activator did not. Akt activation also normalized the aberrant VSMC migration induced by ddC.


CONCLUSIONS
Defective insulin signaling and mitochondrial function may collectively contribute to developing cardiovascular disease.


CONCLUSIONS
Akt may be a possible therapeutic target for treating insulin resistance-associated atherosclerosis.
Ahn
Sun Young
SY
Age-Related and Brain Diseases Research Center, Department of Nanopharmaceutical and Life Sciences, Department of Physiology, Kyung Hee University College of Medicine, Dongdaemoon-Gu Hoegi-Dong #1, Seoul 130-701, Korea.
Choi
Yon-Sik
YS
Koo
Hyun-Jung
HJ
Jeong
Jae Hoon
JH
Park
Wook Ha
WH
Kim
Minseok
M
Piao
Ying
Y
Pak
Youngmi Kim
YK
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000503:physiopathology*; D002465:Cell Movement; D017931:DNA Primers; D003576:Electron Transport Complex IV / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000502:physiology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008099:Liver / Q000502:physiology; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D017931:DNA Primers; D007328:Insulin; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D051057:Proto-Oncogene Proteins c-akt