1,721,030 research outputs found
Structure–activity relationship study of angiotensin II analogs in terms of β-arrestin-dependent signaling to aldosterone production
No full textThe known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion induction, a steroid hormone that contributes to the pathology of postmyocardial infarction (MI) heart failure (HF), is mediated by both Gq/11 proteins and β-arrestins, both of which couple to the AngII type 1 receptors (AT1Rs) of adrenocortical zona glomerulosa (AZG) cells. Over the past several years, AngII analogs with increased selectivity ("bias") toward β-arrestin-dependent signaling at the AT1R have been designed and described, starting with SII, the gold-standard β-arrestin-"biased" AngII analog. In this study, we examined the relative potencies of an extensive series of AngII peptide analogs at relative activation of G proteins versus β-arrestins by the AT1R. The major structural difference of these peptides from SII was their varied substitutions at position 5, rather than position 4 of native AngII. Three of them were found biased for β-arrestin activation and extremely potent at stimulating aldosterone secretion in AZG cells in vitro, much more potent than SII in that regard. Finally, the most potent of these three ([Sar(1), Cys(Et)(5), Leu(8)]-AngII, CORET) was further examined in post-MI rats progressing to HF and overexpressing adrenal β-arrestin1 in vivo. Consistent with the in vitro studies, CORET was found to exacerbate the post-MI hyperaldosteronism, and, consequently, cardiac function of the post-MI animals in vivo. Finally, our data suggest that increasing the size of position 5 of the AngII peptide sequence results in directly proportional increases in AT1R-dependent β-arrestin activation. These findings provide important insights for AT1R pharmacology and future AngII-targeted drug development
Differential Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Suggest GRK5-Mediated Cardio-protection Against Mineralocorticoids
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Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms
No full textβ-Arrestin (βarr)-1 and β-arrestin-2 (βarrs) are universal G-protein-coupled receptor adapter proteins that negatively regulate cardiac β-adrenergic receptor (βAR) function via βAR desensitization and downregulation. In addition, they mediate G-protein-independent βAR signaling, which might be beneficial, for example, antiapoptotic, for the heart. However, the specific role(s) of each βarr isoform in cardiac βAR dysfunction, the molecular hallmark of chronic heart failure (HF), remains unknown. Furthermore, adrenal βarr1 exacerbates HF by chronically enhancing adrenal production and hence circulating levels of aldosterone and catecholamines. Herein, we sought to delineate specific roles of βarr1 in post-myocardial infarction (MI) HF by testing the effects of βarr1 genetic deletion on normal and post-MI cardiac function and morphology. We studied βarr1 knockout (βarr1KO) mice alongside wild-type controls under normal conditions and after surgical MI. Normal (sham-operated) βarr1KO mice display enhanced βAR-dependent contractility and post-MI βarr1KO mice enhanced overall cardiac function (and βAR-dependent contractility) compared with wild type. Post-MI βarr1KO mice also show increased survival and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines and aldosterone, compared with post-MI wild type. The underlying mechanisms, on one hand, improved cardiac βAR signaling and function, as evidenced by increased βAR density and procontractile signaling, via reduced cardiac βAR desensitization because of cardiac βarr1 absence, and, on the other hand, decreased production leading to lower circulating levels of catecholamines and aldosterone because of adrenal βarr1 absence. Thus, βarr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF
Autonomic Dysfunction in Critical Illness: ObNOX(2)ious (Baro)reflex Upregulation of G Protein-Coupled Receptor Kinase-2 Lets the Heart Down.
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Clinical pharmacology of cardiac cyclic AMP in human heart failure: too much or too little?
No full textINTRODUCTION: Cyclic 3\u27, 5\u27-adenosine monophosphate (cAMP) is a major signaling hub in cardiac physiology. Although cAMP signaling has been extensively studied in cardiac cells and animal models of heart failure (HF), not much is known about its actual amount present inside human failing or non-failing cardiomyocytes. Since many drugs used in HF work via cAMP, it is crucial to determine the status of its intracellular levels in failing vs. normal human hearts.
AREAS COVERED: Only studies performed on explanted/excised cardiac tissues from patients were examined. Studies that contained no data from human hearts or no data on cAMP levels per se were excluded from this perspective\u27s analysis.
EXPERT OPINION: Currently, there is no consensus on the status of cAMP levels in human failing vs. non-failing hearts. Several studies on animal models may suggest maladaptive (e.g. pro-apoptotic) effects of cAMP on HF, advocating for cAMP lowering for therapy, but human studies almost universally indicate that myocardial cAMP levels are deficient in human failing hearts. It is the expert opinion of this perspective that intracellular cAMP levels are too low in human failing hearts, contributing to the disease. Strategies to increase (restore), not decrease, these levels should be pursued in human HF
Introduction/General Considerations
No full textThe adrenergic nervous system (ANS) exerts numerous effects on the cardiovascular system, including increase in cardiac contractility (positive inotropy), heart rate acceleration (positive chronotropy), hastened cardiac relaxation (positive lusitropy), and accelerated atrioventricular conduction (positive dromotropy) Most of these effects are mediated by adrenergic receptors (also known as adrenoceptors, ARs), which belong to the guanine nucleotide-binding G-protein-coupled receptor (GPCR) superfamily [1]. GPCRs are heptahelical transmembrane sensors, accounting for approximately 4% of the entire protein-coding genome, widely considered the most important drug targets in physiology and medicine [2]. These receptors consist of seven membrane-spanning domains, three intra- and three extracellular loops, one extracellular N-terminal domain, and one intracellular C-terminal tail [3].https://nsuworks.nova.edu/hpd_corx_facbooks/1013/thumbnail.jp
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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