Adapter proteins and promoter regulation of the angiotensin AT2 receptor — implications for cardiac pathophysiology

Abstract

The angiotensin AT 2 receptor (AT 2 R) represents an important component of the renin-angiotensin system since it is involved in the (patho) physiology of different cardiovascular and neuronal diseases. Furthermore, AT 2 receptors can partly mediate beneficial effects of angiotensin AT 1 receptor (AT 1 R) blockers, and direct pharmacological AT 2 receptor agonism emerges as a novel therapeutic strategy. This review discusses the constitutive and ligand-mediated activity as well as the signal transduction of the AT 2 receptor, focusing on adapter proteins which directly bind to this receptor. Direct protein-protein interaction partners of the AT 2 receptor described so far include the transcription factor promyelocytic zinc finger protein, AT 2 receptor binding protein and the AT 1 receptor. In addition, the putative crosstalk of the AT 2 receptor with the renin/ prorenin receptor (RER) via the promyelocytic zinc finger protein (PLZF) and the role of oestrogens on the regulation of the AT 2 receptor are presented. Conceiving the coupling of the AT 2 receptor to different adapter proteins with distinct and partly opposing cellular effects and the implications of its constitutive activity might help to overcome the current controversies on the (patho)physiological role of the AT 2 receptor.

Angiotensin II type 2 receptor promotes adipocyte differentiation and restores adipocyte size in high-fat/high-fructose diet-induced insulin resistance in rats

“…These discrepancies between SC and RET preadipocytes are of particular interest, since knockdown of AT2R with shRNA had the same effect in both types of adipocytes, indicating that expression of AT2R is essential, but not necessarily its activation. Such a hypothesis may be explained by the constitutive activity of the receptor prior to differentiation (12). In that condition, AT2R action may thus occur through interaction with some of its recently identified partner proteins such as promyelocytic leukemia zinc finger (PLZF) and AT2R-interacting protein (ATIP) (for recent review see Ref.…”

RAS-Mediated Adaptive Mechanisms in Cardiovascular Tissues: Confounding Factors of RAS Blockade Therapy and Alternative Approaches

“…The AT2R is also a GPCR that shares only 34% sequence identity with the AT1R and forms heterodimers with the AT1R [51]. The human AGTR2 gene that codes for the AT2R is located on the X-chromosome and consists of three exons with an uninterrupted coding region that codes a 363-amino-acid receptor in the third exon.…”

The Impact of Overnutrition on Insulin Metabolic Signaling in the Heart and the Kidney

“…AT 2 R signaling reduces fibroblast growth and myocardial hypertrophy [53]. The suppression of AT 2 R activation interferes with anti-hypertrophic/anti-fibrotic effects of AT 1 R blockade in experimental myocardial infarction [54,55,56,57,58]. In cardiomyocyte-specific AT 2 R transgenic mice, moderate overexpression of AT 2 R in ventricular myocytes is cardioprotective under conditions of pressure overload induced by aortic banding [54].…”

“…The association between increases in AT 2 R protein and S6K1 activation in INS-induced cardiac hypertrophy prompts us to posit that mTOR/S6K1-induced increases in translation could, in part, contribute to increases in AT 2 R protein levels. Thus, conditions that activate mTOR-mediated signaling in cardiac tissue could also elevate AT 2 R protein levels [58,59,60]. Activated mTOR nucleates two large protein complexes, mTOR-Raptor complex 1 (mTORC1) and mTOR-Rictor complex 2 (mTORC2) that mediate mTOR signaling.…”