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

Abstract

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. Key Words: renin Ⅲ carotid atheroma Ⅲ type 2 diabetes mellitus Ⅲ MAP-kinase Ⅲ P85-PI3-kinase T ype 2 diabetes mellitus (T2D) is an important risk factor of atherosclerosis, and nearly 80% of diabetic patients die of cardiovascular disease. 1 The inhibition of the renin-angiotensin system (RAS) may be achieved with angiotensin converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT1R) antagonists. These drugs demonstrated a decrease in the mortality and frequency of cardiovascular events, in primary prevention of cardiovascular diseases in high risk patients (Heart Outcomes Prevention Evaluation study [HOPE], Losartan Investigation For Endpoints reduction in hypertension study [LIFE]) and in secondary prevention after myocardial infarction (Gruppo Italiano per lo Studio della Soppravvivenza nell'Infarto miocardico [GISSI3], International Study of Infarct Survival-4 [ISIS4]). [2][3][4] In atherosclerotic regions of arteries, the amounts of immunoreactive ACE and angiotensin II (Ang II) are significantly increased. [5][6][7][8] We previously showed that ACE and other enzymes such as cathepsin G and tissue kallikrein that are able to cleave Ang II from AGT mRNA were also increased in carotid atheroma with a concomitant decrease in AT1R mRNA. 9,10 This suggests that RAS is involved in the atherogenic process. Inhibition of RAS in T2D patients has been shown to be more beneficial than in nondiabetic subjects in terms of reduction of cardiovascular events. 1,2 Moreover, RAS blockers reduced the development of diabetes and insulin resistance in hypertensive patients. 2,11 Thus, RAS is likely to be involved in the development of both insulin resistance and atheroma.Insulin has been shown to activate, via the MAP kinase ERK1-2 pathway, the expression of AGT and AT1R in vascu...

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