In principle, the miRNA duplex could give rise to two different mature miRNAs

In principle, the miRNA duplex could give rise to two different mature miRNAs. Since miRNA SNPs (miRSNPs) can create, destroy, or modify miRNA binding sites, this review focuses on the hypothesis that transcribed target SNPs harbored in RAS mRNAs, that alter miRNA gene regulation and consequently protein expression, may contribute to cardiovascular disease susceptibility. 1. Introduction Identifying the genes and mutations that contribute to disease is a central aim in human genetics. Single nucleotide polymorphisms (SNPs) are mutations that occur at genome positions at Chondroitin sulfate which there are two distinct nucleotide residues (alleles) that each appear in a significant portion (i.e., a minor allele frequency greater than 1%) of the human population [1]. There are some estimated 14 million SNPs [2] in the human genome that occur at a frequency of approximately one in 1,200C1,500?bp [3]. SNPs can affect protein function by changing the amino acid sequences (nonsynonymous SNP) or by perturbing their regulation (e.g., affecting promoter activity [4], splicing process [5], and DNA and pre-mRNA conformation). When SNPs occur in 3-UTRs, they may interfere with mRNA stability and translation by altering polyadenylation and protein/mRNA regulatory interactions. Recently, a new layer of posttranscriptional miRNA-mediated gene regulation has been discovered and shown to control the expression levels of a large proportion of genes (reviewed in [6]). Importantly, SNPs in microRNA (miRNA) target sites (miRSNPs) represent a specific class of regulatory polymorphisms in the 3-UTR that may lead to the dysregulation of posttranscriptional gene expression. Thus, for miRNAs acting by this Chondroitin sulfate mechanism, the miRSNPs may lead to heritable variations in gene expression. Given that the renin angiotensin system (RAS) is intricately involved in the pathogenesis of cardiovascular disease [7C12], we review and discuss the presently available evidence for miRSNPs-mediated RAS gene regulation and its importance for phenotypic variation and disease. 2. Current View of the Renin Angiotensin System The RAS plays a critical role in regulating the physiological processes of the cardiovascular system [reviewed in [7C14]]. The primary effector molecule of this system, angiotensin II (Ang II), has emerged as a critical hormone that affects the function of virtually all organs, including heart, kidney, vasculature, and brain, and it has both beneficial and pathological effects [7C14]. Acute stimulation with Ang II regulates salt/water homeostasis and vasoconstriction, modulating blood pressure, while chronic stimulation promotes hyperplasia and hypertrophy of vascular smooth muscle cells (VSMCs). In addition, long-term exposure to Ang II also plays a pathophysiological role in Chondroitin sulfate cardiac hypertrophy and remodeling, myocardial infarction, hypertension, atherosclerosis, in-stent restenosis, reduced fibrinolysis, and renal fibrosis [7C14]. Ang II, an octapeptide hormone, is produced systemically via the classical RAS and locally via the tissue RAS [7C14]. In the classical RAS, circulating renal-derived renin cleaves hepatic-derived angiotensinogen to form the decapeptide angiotensin I (Ang I), which is converted by angiotensin-converting enzyme (ACE) in the lungs to the biologically active Ang II (Figure 1). Alternatively, a recently identified carboxypeptidase, ACE2, cleaves one amino acid from either Ang I or Ang II [15C18], decreasing Ang II levels and increasing the metabolite Ang 1C7, which has vasodilator properties. Thus, the balance between ACE and ACE2 is an important factor controlling Ang II levels [15C18]. Ang II is also further degraded by aminopeptidases to Ang III (Ang 2C8) and Ang IV (Ang 3C8) (Figure 1) [7]. Although the RAS was originally regarded as a circulating system, many of its components are localized in tissues, including the heart, brain, blood vessels, adrenal, kidney, liver and reproductive organs, indicating the existence of local tissue RASs [19]. In addition to ACE-dependent pathways of Ang II formation, non-ACE pathways have also been described. Chymotrypsin-like serine protease (chymase) may represent an important mechanism for conversion of Ang I to Ang II in the human heart, kidney, and vasculature and may be particularly important in pathological conditions such as coronary heart disease [20]. Open in a separate window Figure 1 Summary of the RAS incorporating the Ang peptide family and physiological effects mediated via ATR subtypes. Under the classical RAS schema, Ang II is produced, via renin and ACE, to act with equal affinity on two ATR subtypes, AT1R and AT2R (large arrows). However, it is now appreciated that a number of breakdown products Chondroitin sulfate of Ang II, Chondroitin sulfate namely, Ang (1C7), Ang III, and Ang IV exert their own unique effects that are distinct (and often opposite) to those of Ang CLDN5 II. Such effects are often mediated via newly recognized receptors such as MasR for Ang (1C7) and AT4R (also known as IRAP) for Ang IV, or additionally via AT2R stimulation. ACE2 is also a new pathway for the formation of Ang (1C7). Newly identified.