Increased insulin-stimulated expression of arterial angiotensinogen and angiotensin type 1 receptor in patients with type 2 diabetes mellitus and atheroma.
OBJECTIVE
Because inhibition of the renin-angiotensin system (RAS) reduces the onset of type 2 diabetes (T2D) and prevents atherosclerosis, we investigated the expression of RAS in the arterial wall of T2D and nondiabetic (CTR) patients.


RESULTS
mRNA and protein levels of angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and AT1 receptor (AT1R) were determined in carotid atheroma plaque, nearby macroscopically intact tissue (MIT), and in vascular smooth muscle cells (VSMCs) before and after insulin stimulation from 21 T2D and 22 CTR patients. AGT and ACE mRNA and their protein levels were 2- to 3-fold higher in atheroma and in MIT of T2D patients. VSMCs from T2D patients had respectively 2.5- and 5-fold higher AGT and AT1R mRNA and protein contents. Insulin induced an increase in AGT and AT1R mRNA with similar ED50. These responses were blocked by PD98059, an inhibitor of MAP-kinase in the two groups whereas wortmannin, an inhibitor of PI3-kinase, partially prevented the response in CTR patients. Phosphorylated ERK1-2 was 4-fold higher in MIT from T2D than from CTR patients.


CONCLUSIONS
The arterial RAS is upregulated in T2D patients, which can be partly explained by an hyperactivation of the ERK1-2 pathway by insulin.
Hodroj
Wassim
W
EA 3740, Functional Genomics in Atherothrombosis, Université de Lyon, Lyon, France.
Legedz
Liliana
L
Foudi
Nabil
N
Cerutti
Catherine
C
Bourdillon
Marie-Claude
MC
Feugier
Patrick
P
Beylot
Michel
M
Randon
Jacques
J
Bricca
Giampiero
G
D000368:Aged; D000704:Analysis of Variance; D000808:Angiotensinogen / Q000096:biosynthesis / Q000187:drug effects*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002340:Carotid Artery Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011336:Probability; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046509:Tissue Culture Techniques; D015854:Up-Regulation
D015415:Biomarkers; D007328:Insulin; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D012313:RNA