The Angiotensin II Type 2 Receptor Causes Constitutive Growth of Cardiomyocytes and Does Not Antagonize Angiotensin II Type 1 Receptor–Mediated Hypertrophy

Abstract

Abstract-Angiotensin II (Ang II) has important actions on the heart via type 1 (AT 1 ) and type 2 (AT 2 ) receptors. The link between AT 1 receptor activation and the hypertrophy of cardiomyocytes is accepted, whereas the contribution of the AT 2 receptor, which reportedly antagonizes the AT 1 receptor, is contentious. This ambiguity is primarily based on in vivo approaches, in which the direct effect of the AT 2 receptor and its modulation of the AT 1 receptor (at the level of the cardiomyocyte) are difficult to establish. In this study, we used adenoviruses encoding AT 1 and AT 2 to coexpress these receptors in isolated cardiomyocytes, allowing a direct examination of the consequence of varying AT 1 /AT 2 stoichiometry on cardiomyocyte hypertrophy. Key Words: angiotensin II Ⅲ hypertrophy Ⅲ myocytes Ⅲ rats Ⅲ receptors L eft ventricular hypertrophy (LVH) is a major independent risk factor for premature death. 1 Extensive experimental and clinical evidence supports a role for the vasoactive hormone angiotensin II (Ang II) in the development of hypertension and the associated cardiomyocyte enlargement, which is a hallmark of LVH. Ang II binds with high affinity to type 1 (AT 1 ) and type 2 (AT 2 ) Ang II receptors, which are 7-transmembrane spanning, G-protein-coupled receptors. 2 AT 1 receptors are well characterized and mediate the established actions of Ang II, including vasoconstriction, aldosterone and vasopressin release, renal sodium reabsorption, increased collagen deposition, cellular proliferation, and, importantly, cardiomyocyte hypertrophy. The role of the AT 2 receptor is less clear, but current theories favor a role in opposing the actions of the AT 1 receptor. 3-7 AT 2 receptors are highly expressed in the fetus; however, after birth, the AT 2 receptor expression decreases to low levels. 2 In normal, adult human and rat hearts, AT 1 and AT 2 receptors are expressed, 8 -10 and they have been shown to be upregulated during cardiovascular pathologies. 8,9 The specific signaling pathways activated via the AT 2 receptor remain poorly resolved, although AT 2 receptors reportedly inhibit AT 1 receptor signaling pathways, such as extracellular signalregulated kinase 1/2 (ERK1/2) mitogen-activated protein kinases (MAPKs), by activating specific tyrosine or serine/ threonine phosphatases. 6,11,12 More recent evidence suggests functional heterodimerization between the AT 1 and AT 2

Alteration of messenger RNA and protein levels of cardiac alpha(1)-adrenergic receptor and angiotensin II receptor subtypes during aging in rats

“…AT 1 R stimulation induced by Ang II influences not only hemodynamics but also promotes hypertrophy of cardiomyocytes, proliferation of fibroblasts and cardiac interstitial fibrosis. AT 2 R has a regulatory role in cardiomyocyte growth and hypertrophy (8,9).…”

Functional interactions between 7TM receptors in the Renin-Angiotensin System—Dimerization or crosstalk?

“…However, this is not always the case. For example, AT2Rs can also promote ligandindependent constitutive hypertrophy in cardiomyocytes (65,66). Even though the AT2R belongs to the family A of the 7TM receptors, and it can in fact signal through G-proteins of the Gαi class (67), much of AT2R signalling probably occur via G-protein independent mechanisms (33,63,67).…”

Angiotensin II–Induced MMP-2 Activity and MMP-14 and Basigin Protein Expression Are Mediated via the Angiotensin II Receptor Type 1–Mitogen-Activated Protein Kinase 1 Pathway in Retinal Pigment Epithelium

“…66,67 These receptor types are coupled to different signal transduction mechanisms. Although there is consensus about the existence of a regular pattern of intracellular pathways regulated by each receptor type, evidence suggests that this pattern may vary depending on a particular tissue or cell type 68,69 Expression of both receptor types (ie, AT1 and AT2) in ARPE-19 cells, mouse RPE, and human retina has been demonstrated. 16 -18,26 Ang II receptor expression has also been confirmed in the RPE-choroid complex in human and mouse choroidal neovascularization tissues 52 .…”