CHANGE IN miRs 145, 221 AND 222 EXPRESSION IN HYPERTENSIVE SUBJECTS TREATED WITH ENALAPRIL, LOSARTAN OR OLMESARTAN

MicroRNAs (miRs), small non-coding RNAs that play key roles in
the regulation of gene expression acting at the post-transcriptional
level, have been indicated as key regulators of several biologic processes,
including cardiovascular disease and protection.
Recently, it was proposed that miRs 221, 222 and 145 may have
a critical role in vascular smooth muscle cell proliferation and
phenotype changes, and in arterial remodelling. miRs 221 and
222 (miRs221/222) modulate cell differentiation and proliferation,
inhibit cell migration and homing, modulate different genes regulating angiogenesis and inflammation, and increase ROS production
promoting atherogenesis. The biological function of miR145
appears to be related to cell proliferation and phenotype. It was
shown that a low miR145 expression promotes smooth muscle cell
switch from contractile to proliferative phenotype, accelerating the
progression of atherosclerosis.
Consistently, it can be proposed that miRs221/222 and miR145
may be involved in the vascular changes occurring due to high
blood pressure; when miR145 and miRs221/222 are balanced, it
results low cell oxidative stress, migration and proliferation, and
slow atherogenesis. Conversely, when miRs221/222 are overexpressed
and miR145 is reduced, there is a trend toward cell migration,
proliferation, cell oxidative stress and atherogenesis.
The aim of the present study was to evaluate whether a treatment
with the anti-hypertensive drugs enalapril, losartan or olmesartan
may have effects on the monocyte expression of miRs 145, 221
and 222 in hypertensive subjects without organ involvement. We
included 64 hypertensives with no additional risk factor for CVD
and 42 matched controls; we evaluated blood pressure values, lipid
profile, fasting glucose, C-reactive protein (CRP), Fibrinogen,
arterial stiffness (AS) indices, including pulse way velocity (PWV)
and augmentation index (AIx) and carotid intima-media thickness
(cIMT) at baseline (T0) and after 24-weeks treatment (T1). Patients
included in the study were already pre-screened to exclude
secondary hypertension. Subjects with plasma levels of total cholesterol
(TC) ≥230 mg/dl or low-density lipoprotein cholesterol
(LDL-C) ≥160 mg/dl, triglycerides (TG) ≥200 mg/dl, body mass
index (BMI) ≥30, alcohol consumption, a personal or familial history
of CVD, diabetes mellitus, or thyroid, liver or kidney diseases
were excluded.
After inclusion, patients were randomly assigned to receive once
a day enalapril 20 mg (E), losartan 100 mg (L) or olmesartan 20
mg (O). Comparisons were carried out by paired measures Wilcoxon
test (T1 vs T0), Kruskall-Wallis (multiple comparisons), and
Mann-Whitney (comparisons between pairs of treatment arms). A
two tailed p of 0.05 was considered for significance.
At T1, we found a significant improvement of both systolic and
diastolic blood pressure (SBP: -19.03%, p<0.001; DBP: -14.41%,
p<0.001), lipid profile (TC: -2.7%, p<0.001; TG: +1.7%, p=ns; HDL-C:
+4.4%, p<0.001; LDL-C: -6.4%, p<0.001), fasting glucose (-2.5%,
p<0.001), BMI (-3.1%, p<0.001), Fibrinogen (-6.2%, p<0.001), CRP
(-9.2%, p<0.005), AS indices (AIx: -19.1%, p<0.001; PWV: -14.4%,
p<0.001), and monocyte miR expression (miR221: -29.8%, p<0.001;
miR222: -39.7%, p<0.001; miR145: +41.1%, p<0.001)
We then have analyzed separately each arm of treatment, and
compared the effects of each treatment on the different variables.
Olmesartan appeared the most effective in reducing CRP levels
(-9.48%), and miRs221/222 (-32.9% and -42.4%, respectively); losartan
reduced PWV (-37.6%) and improved HDL-C levels (+7.9%) and
miR145 (+51.5%) more than olmesartan and enalapril; enalapril
appeared more effective on fibrinogen reduction (-9%); no differences
were found with regard to BMI, fasting glucose, TC,