Article: article from journal or magazin.
Increased insulin-stimulated expression of arterial angiotensinogen and angiotensin type 1 receptor in patients with type 2 diabetes mellitus and atheroma.
Arteriosclerosis Thrombosis and Vascular Biology
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
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. METHODS AND 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.
Aged, Analysis of Variance, Angiotensinogen/biosynthesis, Angiotensinogen/drug effects, Atherosclerosis/etiology, Atherosclerosis/metabolism, Biological Markers/metabolism, Blotting, Western, Carotid Artery Diseases/etiology, Carotid Artery Diseases/metabolism, Diabetes Mellitus, Type 2/complications, Diabetes Mellitus, Type 2/drug therapy, Endothelium, Vascular/drug effects, Endothelium, Vascular/metabolism, Female, Gene Expression Regulation, Humans, Insulin/pharmacology, Male, Middle Aged, Probability, RNA/metabolism, RNA, Messenger/analysis, Receptor, Angiotensin, Type 1/metabolism, Renin-Angiotensin System/drug effects, Renin-Angiotensin System/physiology, Reverse Transcriptase Polymerase Chain Reaction, Tissue Culture Techniques, Up-Regulation
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