Angiotensin Receptor Blocker Drugs and Inhibition of Adrenal Beta-Arrestin-1-Dependent Aldosterone Production: Implications for Heart Failure Therapy

Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II (AngII). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure (HF), is induced by AngII type 1 receptors (AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1 (βarr1) or -2 (βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 protein-independent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers (ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes (G protein-, and βarr1-dependent) at the AngII-activated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by AngII and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-“biased” blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan (and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone

Impaired desensitization of a human polymorphic α2B-adrenergic receptor variant enhances its sympatho-inhibitory activity in chromaffin cells

<p>Abstract</p> <p>Background</p> <p>α₂-adrenergic receptors (ARs) mediate many cellular actions of epinephrine and norepinephrine and inhibit their secretion from adrenal chromaffin cells. Like many other G-protein coupled receptors (GPCRs), they undergo agonist-dependent phopshorylation and desensitization by GPCR Kinases (GRKs), a phenomenon recently shown to play a major role in the sympathetic overdrive that accompanies and aggravates chronic heart failure. A deletion polymorphism in the human α_2B-AR gene (Glu301-303) causes impaired agonist-promoted receptor phosphorylation and desensitization in heterologous cell lines. Given the importance of α₂-ARs in regulation of catecholamine secretion from chromaffin cells, we sought to investigate, in the present study, the desensitization properties and the sympatho-inhibitory activity of this variant in a chromaffin cell line. For this purpose, we expressed this variant and its wild type counterpart in the well-established chromaffin cell line PC12, and performed receptor phosphorylation and desensitization studies, as well as in vitro catecholamine secretion assays.</p> <p>Results</p> <p>Both the agonist-induced phosphorylation and agonist-dependent desensitization of the human Glu301-303 deletion polymorphic α_2B-AR are significantly impaired in PC12 cells, resulting in enhanced signaling to inhibition of cholinergic-induced catecholamine secretion in vitro.</p> <p>Conclusion</p> <p>This α_2B-AR gene polymorphism (Glu301-303 deletion) might confer better protection against conditions characterized and aggravated by sympathetic/catecholaminergic overstimulation in vivo.</p

Town Meeting: A Representative but Non-Sovereign Institution

Questions of democracy are fundamental for modern society. One of the main distinctions made in the study of democracy is between direct and representative democracy. While most democratic institutions today are representative, the roots of democracy lie in direct democracy, a system in which citizens vote directly on the issues rather than on candidates who will then make the decisions. One of the most historically significant institutions in the area of direct democracy, especially in the American tradition, is the town meeting. Unfortunately, most of the discussion on the town meeting has focused on the question of representation (for example attendance rates at meetings) resulting in a substitution of a broad discussion on democracy with a narrow discussion on representation. The aim of this thesis is not only to illustrate this issue, but also to indicate how the addition of another axis of analysis, power-external/sovereignty, can untangle some of the confusing aspects of the existing narratives regarding the town meeting. The thesis draws upon a variety of documents, such as 17th century town meeting records, the writings of Thomas Jefferson, a 20th century radio show, and present day news articles, in order to aid in the reconceptualization of core issues such as power and representation, as well as to provide new insights in topics such as the use of direct democracy for purposes of political education. The hope is to inspire more advances in our understanding of the limitations and shortcomings of our current framework of analysis for the town meeting, as well as to introduce different perspectives of analysis which, in combination with representation and power, can provide a more holistic understanding of the town meeting institution.</p

An adrenal beta-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo.

Aldosterone produces a multitude of effects in vivo, including promotion of postmyocardial infarction adverse cardiac remodeling and heart failure progression. It is produced and secreted by the adrenocortical zona glomerulosa (AZG) cells after angiotensin II (AngII) activation of AngII type 1 receptors (AT(1)Rs). Until now, the general consensus for AngII signaling to aldosterone production has been that it proceeds via activation of G(q/11)-proteins, to which the AT(1)R normally couples. Here, we describe a novel signaling pathway underlying this AT(1)R-dependent aldosterone production mediated by beta-arrestin-1 (betaarr1), a universal heptahelical receptor adapter/scaffolding protein. This pathway results in sustained ERK activation and subsequent up-regulation of steroidogenic acute regulatory protein, a steroid transport protein regulating aldosterone biosynthesis in AZG cells. Also, this betaarr1-mediated pathway appears capable of promoting aldosterone turnover independently of G protein activation, because treatment of AZG cells with SII, an AngII analog that induces betaarr, but not G protein coupling to the AT(1)R, recapitulates the effects of AngII on aldosterone production and secretion. In vivo, increased adrenal betaarr1 activity, by means of adrenal-targeted adenoviral-mediated gene delivery of a betaarr1 transgene, resulted in a marked elevation of circulating aldosterone levels in otherwise normal animals, suggesting that this adrenocortical betaarr1-mediated signaling pathway is operative, and promotes aldosterone production and secretion in vivo, as well. Thus, inhibition of adrenal betaarr1 activity on AT(1)Rs might be of therapeutic value in pathological conditions characterized and aggravated by hyperaldosteronism

NovelCraft: A Dataset for Novelty Detection and Discovery in Open Worlds

In order for artificial agents to successfully perform tasks in changing environments, they must be able to both detect and adapt to novelty. However, visual novelty detection research often only evaluates on repurposed datasets such as CIFAR-10 originally intended for object classification, where images focus on one distinct, well-centered object. New benchmarks are needed to represent the challenges of navigating the complex scenes of an open world. Our new NovelCraft dataset contains multimodal episodic data of the images and symbolic world-states seen by an agent completing a pogo stick assembly task within a modified Minecraft environment. In some episodes, we insert novel objects of varying size within the complex 3D scene that may impact gameplay. Our visual novelty detection benchmark finds that methods that rank best on popular area-under-the-curve metrics may be outperformed by simpler alternatives when controlling false positives matters most. Further multimodal novelty detection experiments suggest that methods that fuse both visual and symbolic information can improve time until detection as well as overall discrimination. Finally, our evaluation of recent generalized category discovery methods suggests that adapting to new imbalanced categories in complex scenes remains an exciting open problem.Comment: Published in Transactions on Machine Learning Research (03/2023