Molecular Mechanisms and Carotid Atherosclerosis
Molecular Mechanisms and Carotid Atherosclerosis
The role of methylase system in the accelerated atherosclerotic progression of diabetic
 patients is unclear. Authors will evaluate methylase activity in carotid plaques of
 asymptomatic diabetic and non diabetic patients, as well as the effect of metformin in
 diabetic plaques. Plaques will be obtained from 46 type 2 diabetic and 30 non diabetic
 patients undergoing carotid endarterectomy. Diabetic patients will receive 1000 mg of
 metformin (n 23) or placebo (n 23) for 4 months before scheduled endarterectomy. Plaques will
 be analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLADR), methylase
 activity, nuclear factor (NF)-KB, tumor necrosis factor (TNF)-alpha, nitrotyrosine, matrix
 metalloproteinase (MMP) and collagen content (immunohistochemistry and enzyme- linked
 immunosorbent assay. Authors' study hypothesis is that methylase over-activity will be
 associated with enhanced inflammatory reaction and NF-KB expression in diabetic plaques.
 Secondly, the inhibition of methylase activity in atherosclerotic lesions of diabetic
 patients by metformin might be associated with morphological and compositional
 characteristics of a potential stable plaque phenotype, possibly by down regulating
 NF-KB-mediated inflammatory pathways.
Diabetes Mellitus (DM) leads to increased vulnerability for plaque disruption and mediates
 increased incidence and severity of clinical events. Inflammation, particularly in diabetes,
 plays a central role in the cascade of events that result in plaque erosion and fissuring.
 There is emerging evidence that the methylase system might be involved in both initial stage
 and progression of atherosclerosis. Moreover, the methylase system might be involved in
 inflammatory/oxidative stress pathway, involved for activation of nuclear factor kappa B
 (NF-KB), and other proteins linked to over inflammation/oxidative stress. Although it has
 been demonstrated that diabetes may up regulate these inflammatory/oxidative pathway, still
 no evidence exists about the potential role of methylase system in the evolution of
 atherosclerotic plaques of diabetic patients. Conversely, less data have been reported about
 the possible modulation of these pathways by hypoglycemic drugs as oral metfromin. However,
 in the present study authors hypothesized that by increasing methylase activity, diabetes may
 enhance the inflammatory potential of atherosclerotic plaques favoring instability.
 Therefore, authors designed this study to identify differences in inflammatory infiltration
 as well as methylase activity between carotid plaques of asymptomatic diabetic and non
 diabetic (normoglycemics) patients. Because experimental and pathological studies suggest
 that activation of methylase system might control inflammation/oxidative stress, the present
 study also evaluated the effect of the metformin on methylase activity in carotid plaques of
 diabetic patients.
Inclusion Criteria:

 -  evidence of carotid artery atherosclerosis with endoluminal stenosis > 60%;

 -  aged >18 years.

 -  aged <75 years

 Exclusion Criteria:

 -  insulin dependent DM;

 -  absence of carotid artery atherosclerosis with endoluminal stenosis > 60%;

 -  contraindication to receive a carotid artery revascularization treatment;

 --contraindication to receive metformin treatment;

 -  neoplastic diseases;