EXPRESSION OF MIRS 221, 222 AND 145 IN PERIPHERAL MONOCYTE CELLS OF ESSENTIAL HYPERTENSIVE PATIENTS

MicroRNAs (miRs) are highly conserved, short noncoding RNA molecules that negatively regulate messenger RNA stability and/ or translational efficiency. Since miRs can control the expression of many genes, their role appears central to the survival and functions of many cells. Several miRs have been associated with cardiovascular disease and protection. miRs 221 and 222 (miR221/222) have been already identified in several different cells types including endothelial cells, circulating progenitor cells, and peripheral monocytes. In these cell types miR221/222 participate in the differentiation and proliferation, inhibiting cell migration and homing, also by inhibiting the synthesis of the receptor for the Stem Cell Factor c-Kit. Moreover, miR221/222 modulate different genes regulating the angiogenesis and inflammation. We have already observed that miR221/222 were up-regulated in CVD patients increasing ROS production and reducing angiogenesis. miR145 was described in smooth muscle cells (SMCs), and more recently also in peripheral monocyte cells, and its biological function appears to be related to cell proliferation and phenotype. It was shown that when miR145 is under-expressed, SMCs switch from contractile to proliferative phenotype, accelerating the progression of atherosclerosis. Consistently, it can be proposed that miRs221/222 and miR145 act in an opposite manner: low miR145 expression with high miRs221/222 expression promoting a trend toward cell migration, proliferation, cell oxidative stress and atherogenesis; conversely, a balanced miR145 and miRs221/222 expression result in lower cell oxidative stress, cell migration and proliferation, and deceleration of atherogenesis. We evaluated the expression of miRs 145, 221 and 222 in peripheral blood monocytes (Real Time-PCR) in 64 consecutively enrolled newly diagnosed, untreated hypertensive patients (aged between 21 and 52 years old) with no additional risk factors; 49 healthy subjects were included as controls. Plasma lipids, fibrinogen and C-reactive protein (CRP) levels, AS indices, including pulse way velocity (PWV) and augmentation index (AIx) and carotid media thickness (cIMT) were measured. We found that on the average hypertensives presented with approximately 2-fold miR221/222 expression, whereas miR145 was approximately 0.75-fold with respect to healthy controls. Furthermore, miR expression correlates with several markers of vascular involvement and risk factors. Total cholesterol (221: r=0.358, p<0.005; 222: r=0.242, p<0.05; 145: r=-0.253, p<0.05), High density lipoprotein-cholesterol (221: r=-0.618, p<0.001; 222: r=-0.693, p<0.001; 145: r=0.645, p<0.001), Low density lipoprotein-cholesterol (221: r=0.459, p<0.001; 222: r=0.349, p<0.005; 145: r=-0.353, p<0.005), Fibrinogen (221: r=0.589, p<0.001; 222: r=0.774, p<0.001; 145: r=-0.661, p<0.01), CRP (221: r=0.429, p<0.001; 222: r=0.566, p<0.001; 145: r=-0.462, p<0.001), Systolic blood pressure (221: r=0.627, p<0.001; 222: r=0.543, p<0.001; 145: r=-0.571, p<0.001), Diastolic blood pressure (221: r=0.534, p<0.001; 222: r=0.543, p<0.001; 145: r=-0.613, p<0.001), AIx 221: r=0.651, p<0.001; 222: r=0.701, p<0.001; 145: r=-0.620, p<0.001, PWV (221: r=0.693, p<0.001; 222: r=0.726, p<0.001; 145: r=-0.641, p<0.001), cIMT (221: r=0.397, p<0.001; 222: r=0.443, p<0.001; 145: r=-0.456, p<0.001). Multiple regression analysis indicated that miR145, miR221 and miR222 expression are significantly influenced by Fibrinogen, SBP and DBP; moreover, miR222 is also associated with CRP plasma levels (p<0.001), and AS indices (AIx: p<0.001, PWV: p<0.005). Although we found an inverse correlation between miR145 and miRs221/222, miR145 showed a poor absolute predictive power with respect to vascular indices. In conclusion we can confirm the role of miR221/222 in modulating vascular response to high blood pressure-induced damaging, and also suggest miR145 as potential marker of counter-regulatory system.