Search

Background: Essential hypertension is considered to be a multifactorial disorder and its aetiology has yet to be clearly identified. As the adenosine receptors have a significant role in mediating vasodilation, alterations in their structures or signalling pathways may be involved in the development of hypertension. This study aimed to measure the expression of adenosine A3 receptors in a range of cardiovascular tissues and determine whether they could be altered with essential hypertension, and to functionally test responses to adenosine A3 receptor agonists in coronary blood vessels using the isolated perfused heart preparation. Methods: mRNA samples from cardiovascular tissues and a range of blood vessels were collected from 10 week old male spontaneously hypertensive rats and age-gender matched Wistar rats (n = 8). The Langendorff heart perfusion preparation was used to characterise adenosine A3 receptor mediated coronary vasodilation in the rat heart. Results: Adenosine A3 receptor agonists induced coronary vasodilation. The expression of adenosine A3 receptors in cardiovascular tissues was altered in a tissue-specific pattern. Specifically, down-regulation of adenosine A3 receptor expression occurred in hypertensive hearts, which might be associated with attenuated vasodilator responses observed in coronary vessels to adenosine A3 receptor agonists. Conclusions: This study demonstrated alterations in the expression of adenosine A3 receptors occurred in a tissue specific mode, and reduced adenosine A3 receptor mediated coronary vasodilation in hearts from spontaneously hypertensive rats. Our findings with regard to changes in the adenosine A3 receptor in hypertensive hearts suggest that adenosine A3 receptor might play a role in the physiopathology of essential hypertension and potentially open the way to pharmacologic manipulation of vasomotor activity by the use of adenosine A3 receptor agonists. [ABSTRACT FROM AUTHOR]

T-cell leukemia 1A ( TCL1A ) single-nucleotide polymorphisms (SNPs) have been associated with aromatase inhibitor-induced musculoskeletal adverse events. We previously demonstrated that TCL1A is inducible by estradiol (E 2 ) and plays a critical role in the regulation of cytokines, chemokines, and Toll-like receptors in a TCL1A SNP genotype and estrogen-dependent fashion. Furthermore, TCLIA SNP-dependent expression phenotypes can be "reversed" by exposure to selective estrogen receptor modulators such as 4-hydroxytamoxifen (4OH-TAM). The present study was designed to comprehensively characterize the role of TCL1A in transcriptional regulation across the genome by performing RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) assays with lymphoblastoid cell lines. RNA-seq identified 357 genes that were regulated in a TCL1A SNP- and E 2 -dependent fashion with expression patterns that were 4OH-TAM reversible. ChIP-seq for the same cells identified 57 TCL1A binding sites that could be regulated by E 2 in a SNP-dependent fashion. Even more striking, nuclear factor- κ B (NF- κ B) p65 bound to those same DNA regions. In summary, TCL1A is a novel transcription factor with expression that is regulated in a SNP- and E 2 -dependent fashion-a pattern of expression that can be reversed by 4OH-TAM. Integrated RNA-seq and ChIP-seq results suggest that TCL1A also acts as a transcriptional coregulator with NF- κ B p65, an important immune system transcription factor., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

This review describes the important functional implications of TCL1A single nucleotide polymorphisms (SNPs) discovered during pharmacogenomic studies of aromatase inhibitor-induced musculoskeletal adverse events that were subsequently shown to influence the expression of cytokines, chemokines, toll-like receptors (TLR), and NF-κB in a SNP and estrogen-dependent fashion. Functional genomic studies of these SNPs led to the discovery of novel mechanisms that may contribute to disease pathophysiology and which may also increase our understanding of pharmacogenomic aspects of regulation of the expression of inflammatory mediators. Specifically, TCL1A expression was induced by estrogens in a SNP-dependent fashion, resulting in downstream effects on the expression of immune mediators that included IL17RA, IL17A, CCR6, CCL20 TLR2, TLR7, TLR9, TLR10 and NF-κB. These observations have potential implications for inflammatory diseases such as rheumatoid arthritis-a disease for which two thirds of patients are women. Strikingly, this genomic phenomenon could be "reversed" by estrogen receptor antagonist treatment-once again in a SNP-dependent, i.e., in a pharmacogenomic fashion. Specifically, differential SNP-dependent effects on estrogen receptor binding to estrogen response elements before and after estrogen receptor blockade might be associated with mechanisms underlying the SNP genotype and estrogen-dependent regulation of TCL1A and the expression of downstream immune mediators. Furthermore, this SNP and estrogen-dependent phenotypic response could be "reversed" by SERM treatment. These observations could potentially open the way to understand, predict and even pharmacologically manipulate the expression of selected immune mediators in a SNP-dependent fashion., Competing Interests: Conflict of Interest: No conflicts declared.

In a previous genome-wide association study (GWAS) for musculoskeletal adverse events during aromatase inhibitor therapy for breast cancer, we reported that single nucleotide polymorphisms (SNPs) near the TCL1A gene were associated with this adverse drug reaction. Functional genomic studies showed that TCL1A expression was induced by estradiol, but only in cells with the variant sequence for the top GWAS SNP (rs11849538), a SNP that created a functional estrogen response element. In addition, TCL1A genotype influenced the downstream expression of a series of cytokines and chemokines and had a striking effect on nuclear factor κ B (NF- κ B) transcriptional activity. Furthermore, this SNP-dependent regulation could be reversed by selective ER modulators (SERMs). The present study was designed to pursue mechanisms underlying TCL1A SNP-mediated, estrogen-dependent NF- κ B activation. Functional genomic studies were performed using a panel of 300 lymphoblastoid cell lines for which we had generated genome-wide SNP and gene expression data. It is known that toll-like receptors (TLRs) can regulate NF- κ B signaling by a process that requires the adaptor protein MYD88. We found that TLR2, TLR7, TLR9, and TLR10 expression, as well as that of MYD88, could be modulated by TCL1A in a SNP and estrogen-dependent fashion and that these effects were reversed in the presence of SERMs. Furthermore, MYD88 inhibition blocked the TCL1A SNP and estrogen-dependent NF- κ B activation, as well as protein-protein interaction between TCL1A and MYD88. These observations greatly expand the range of pathways influenced by TCL1A genotype and raise the possibility that this estrogen- and SNP-dependent regulation might be altered pharmacologically by SERMs., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)