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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:525.)
© 2007 American Heart Association, Inc.

Vascular Biology

Increased Insulin-Stimulated Expression of Arterial Angiotensinogen and Angiotensin Type 1 Receptor in Patients With Type 2 Diabetes Mellitus and Atheroma

Wassim Hodroj; Liliana Legedz; Nabil Foudi; Catherine Cerutti; Marie-Claude Bourdillon; Patrick Feugier; Michel Beylot; Jacques Randon; Giampiero Bricca

From EA 3740, Functional Genomics in Atherothrombosis (W.H., L.L., N.F., C.C., M.-C.B., P.F., J.R., G.B.); Université de Lyon; Université Claude Bernard Lyon1; and INSERM U499 (M.B.), Lyon, France.

Correspondence to Giampiero Bricca, EA 3740 Génomique fonctionnelle dans l’athéro-thrombose, Université Claude Bernard Lyon 1, IFR62, INSERM, rue Guillaume Paradin, 69372 Lyon cedex 08, France. E-mail bricca{at}lyon.inserm.fr

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.

The involvement of local angiotensin system in atherosclerosis of type 2 diabetes was investigated in carotid endarterectomy specimens and derived VSMCs. We have shown basal overexpression of angiotensinogen and angiotensin type-1 receptor in carotid wall as well as an exaggerated insulin-induced stimulation of this expression in VSMCs from these patients.

Key Words: renin • carotid atheroma • type 2 diabetes mellitus • MAP-kinase • P85-PI3-kinase

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