Angiotensin II Type 1 Receptor Gene Regulation

Abstract

A ngiotensin II (Ang II), the major bioactive peptide of the renin-angiotensin system, was originally described as a potent vasoconstrictor. It is now recognized as a multifunctional hormone influencing many cellular processes, including cell growth, apoptosis, migration, inflammation, and fibrosis. 1,2 Under pathological conditions, the vasoconstrictor, mitogenic, proinflammatory, and profibrotic actions of Ang II contribute to altered vascular tone, structural remodeling, and endothelial dysfunction. [3][4][5][6] Thus, Ang II plays a key role in the pathogenesis of cardiovascular diseases.The biological responses of Ang II are mediated by its interaction with 2 distinct high-affinity G protein-coupled receptors now designated Ang II type 1 receptor (AT 1 R) and Ang II type 2 receptor. 7 Most of the known physiological and pathophysiological effects of Ang II are mediated via the AT 1 R. [1][2][3][4][5][6][7] This receptor subtype is expressed in cardiovascular-relevant cell types including vascular smooth muscle cells (VSMCs), endothelial cells, cardiac myocytes, cardiac fibroblasts, and renal mesangial cells. 7 The multiple actions of Ang II, mediated through the AT 1 R, are a result of complex intracellular signaling pathways including stimulation of the phospholipase C/inositol 1,4,5-trisphosphate/diacylglycerol cascade, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases, tyrosine kinases, and RhoA/Rho kinase. 1,2,4,6,7 In addition, AT 1 Rs mediate many of their pathophysiological effects by stimulating reactive oxygen species generation via an reduced nicotinamide-adenine dinucleotide/reduced nicotinamide-adenine dinucleotide phosphate oxidase-dependent mechanism. 2,8 Reactive oxygen species, in turn, influences downstream signaling molecules, including transcription factors, tyrosine kinases/phosphatases, Ca 2ϩ channels, and MAPKs. 2,8 The expression level of the AT 1 R defines the biological efficacy of Ang II; hence, overexpression of the AT 1 R is one potential mechanism by which Ang II can contribute to cardiovascular disease. Importantly, aberrant expression of the AT 1 R has been shown to have pathophysiological relevance in cell culture, animal studies, and in clinical interventional trails (reviewed in Reference 5). This review will summarize the transcriptional and posttranscriptional mechanisms by which AT 1 R gene expression is regulated and discuss the pathological relevance of these mechanisms in mediating cardiovascular disease. AT 1 R Gene StructureTo initiate the investigations into the mechanisms by which AT 1 R expression is regulated, the AT 1 R gene has been cloned from a variety of species. Uniquely, the rodent genome harbors 2 distinct AT 1 R genes: AT 1A R and AT 1B R. 9 -15 The AT 1A R gene has been localized to chromosomes 17 and 13 of the rat and mouse, respectively, whereas the AT 1B R gene has been localized to chromosomes 2 and 3 of the rat and mouse, respectively. 14,15 It has been suggested that both receptor subtypes are pharmacologically and fu...

Posttranscriptional regulation of angiotensin II type 1 receptor expression by glyceraldehyde 3-phosphate dehydrogenase

“…Cell surface expression of AT1R is regulated by receptor internalization and this is modulated by multiple proteins including arrestins and ATRAP (4). Transcriptional regulators of AT1R gene include glucocorticoids and interleukin 1β (5). Posttranscriptional regulation of the AT1R mRNA transcript has been established to be an important regulatory mechanism of AT1R expression by insulin, statins and estrogen (6–11).…”

Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y 2 receptor stimulation through S-nitrosylation of NF-κB

“…A large number of studies have shown that a wide range of physiological and pathological stimuli modulate AT 1 R expression in a number of cell types and tissues (40). We first demonstrated that ATP induces down-regulation of AT 1 R signaling in rat cardiac fibroblasts.…”

Functional Relevance of Biased Signaling at the Angiotensin II Type 1 Receptor

“…The AT1R overexpression studies discussed in the preceding paragraph each utilized AT1 A R, which may reflect the endogenous response to AT1R ligand stimulation, but leaves the effect of tissue-specific AT1R subtype expression on EGFR transactivation unexplored. Additionally, AT1R subtype expression may not necessarily depend solely on the tissue type, but could be influenced by pathophysiologic conditions or developmental stage [68], thereby impacting EGFR transactivation. Indeed, studies using rat cardiac fibroblasts at distinct stages of development have reported different abilities of AT1R to mediate EGFR transactivation.…”