4. Conclusion

findings. Association with hypertension was established in a certain subgroups of patients, e.g. only in subjects with severe, early onset, form of disease [142] and in long-term-treated subjects and/or with a family history of hypertension (HT) [143, 144] or in subjects with hypercholesterolaemia [145] or in males only [146]. A systematic review and a meta-analysis of the rs5186 variant failed to present sufficient evidence that polymorphisms in the AT1R gene are risk

Besides hypertension, rs5186 was associated with increased reactivity to Ang II in human arteries [148] and blood pressure response to exogenous Ang II [149]. In the context of atherosclerosis and different atherosclerotic phenotypes, previous studies addressed this polymorphism with inconsistent data. Some failed to show any significant effect for the A1166C polymorphism on mean IMT, carotid plaque formation [150] or internal carotid artery (ICA) stenosis [151]. The C-allele has been associated with a thicker carotid IMT in women [152] and increased IMT and IMT/D (common carotid artery diameter) ratio in hypertensive subjects [153]. A meta-analysis performed in 2011 suggests that the AT1R gene A1166C polymorphism is not associated with susceptibility to ischemic stroke [154]. However, the association between the AT1R 1166C allele and the presence of hypoechoic carotid plaques was recently found [155]. Confronting results could be attributed to differences in age, gender, belonging to different populations or ethnic groups, or different non-genomic and other external factors. The AT1R A1166C polymorphism is positioned in the target site for miR-155 [156, 157]. It was shown experimentally that human miR-155 downregulates expression of the 1166A allele alone [156], and that interaction between authentic miR-155 and the C allele is diminished, in a way that its ability to regulate AT1R gene expression is

The AT2R, -1332 A/G polymorphism (rs1403543) located within the intron 1 of the gene was proposed to be functional, by affecting the mRNA alternative splicing and gene expression of AT2R. However, novel findings suggest that -1332 A/G might modulate protein expression, but not mRNA splicing [158, 159]. There are few studies that have been investigating this polymorphism in association with the presence of atherosclerotic plaques. Our study performed recently suggests that AT2R -1332 A/G polymorphism is a reliable gender-specific risk factor for carotid atherosclerotic plaque presence in females and could modify the interindividual risk of cerebrovascular insult (CVI) among males with advanced carotid atherosclerosis [160]. It is still not clear which of the alleles, A or G, are more likely to carry a significant risk, even for hypertension and different cardiovascular phenotypes that were reproducibly investigated [161]. It was shown that a -1332 A/G polymorphism represents a risk factor for cardiovascular diseases and severe atherosclerosis by modifying systemic inflammation, especially in hypertensive males [162]. It is known that AT2R is expressed at low levels in the healthy adult vasculature. AT2R effects on cardiovascular structure and function may only become detectable under pathological conditions and/or after AT1R blockade. Expression of AT2R in human carotid atherosclerotic plaques was previously detected [163]. However, whether the stimulation of the AT2R is protective or deleterious in human atherosclerosis remains unresolved. The impact of AT2R during atherosclerosis or tissue injury should be studied by direct stimulation of AT2R to address potential therapeu-

factors for hypertension [147].

24 Renin-Angiotensin System - Past, Present and Future

altered [157].

tic potential [164, 165].

Activation of RAS in the vascular wall has modulatory activities in the development of atherosclerosis by stimulating a series of cellular and molecular events. The balance between activation and repression of RAS could be decisive in the pathological remodelling, endothelial dysfunction and pathogenesis of atherosclerosis. Unfavorable and favorable effects of RAS molecules and their genetic variations, as well as consequently induced pathways, affect atherosclerosis development and following clinical events. This could have potential towards clinical application for risk stratification and therapeutics.
