β-Arrestin as a Therapeutic Target in Heart Failure

Boussi, Leora; Frishman, William H.

doi:10.1097/crd.0000000000000363

Cited by 11 publications

(8 citation statements)

References 79 publications

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Section: Discussionsupporting

confidence: 93%

“…In addition, the mRNA level of ARRB2 with rs75428611-G was also higher than A allele using human lymphocytes. Our results demonstrated the fact that ARRB2 expression level was positively correlated to prognosis of HF patients, which favors the protective role of ARRB2 in HF and is in line with previous reports [23,24]. However, recent study conducted by Wang et al [7] has found that ARRB2 could mediate cardiac ischemiareperfusion injury by inhibiting GPCR-independent cell survival signaling.…”

Section: Discussionsupporting

confidence: 92%

“…Importantly, ARRB2 has been identified to function as scaffold proteins linking GPCR activation to several downstream effectors in G-protein-independent signaling [11]. Under the condition of HF, ARRB2 could relieve the deleterious response to excessive sympathetic stimulation through attenuating β-adrenergic and angiotensin II receptor signaling while simultaneously preserving cardiac structure and function by transactivating cardioprotective signaling cascades in response to injury [23]. For example, Noma et al [16] have demonstrated the protective role of ARRB2-mediated β1-adrenergic receptor transactivation of the EGFR [24].…”

Section: Discussionmentioning

confidence: 99%

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A Common Variant of ARRB2 Promoter Region Associated with the Prognosis of Heart Failure

Ren¹,

Liu²,

Tan³

et al. 2023

Hum Hered

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Introduction The role of ARRB2 in cardiovascular disease has recently gained increasing attention. However, the association between ARRB2 polymorphisms and heart failure (HF) has not yet been investigated. Methods A total of 2386 hospitalized patients with chronic heart failure were enrolled as the first cohort and followed up for a mean period of 20.2 months. Meanwhile, ethnically and geographically matched 3000 individuals without evidence of HF were included as healthy controls. We genotyped the common variant in ARRB2 gene to identify the association between variant and HF. A replicated independent cohort enrolling 837 patients with chronic HF was applied to validate the observed association. A series of function analysis were conducted to illuminate the underlying mechanism. Results We identified a common variant rs75428611 associated with the prognosis of HF in two-stage population: adjusted P = 0.001, HR = 1.31 (1.11-1.54) in additive model and adjusted P = 0.001, HR = 1.39 (1.14-1.69) in dominant model in first-stage population; adjusted P = 0.04, HR = 1.41 (1.02-1.95) in additive model and adjusted P = 0.03, HR = 1.51 (1.03-2.20) in dominant model in replicated stage. However, rs75428611 did not significantly associate with the risk of HF. Functional analysis indicated that rs75428611‐G allele increased the promoter activity and the mRNA expression level of ARRB2 by facilitating transcription factor SRF binding, but not the A allele. Conclusions Our findings demonstrate that rs75428611 in promoter of ARRB2 is associated with the risk of HF mortality. It is a promising potential treatment target for HF.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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A Common Variant of ARRB2 Promoter Region Associated with the Prognosis of Heart Failure

Ren¹,

Liu²,

Tan³

et al. 2023

Hum Hered

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“…Biased signaling occurs when different ligands, upon interaction with a given receptor, trigger distinct signaling pathways and responses . Biased ligands for AT 1 Rs are well documented, with several prototypical analogues biased toward G protein activation or β-arrestin (βarr) recruitment. − For instance, TRV027 induces βarr recruitment (equivalent in magnitude to that observed for Ang II) while antagonizing Ang II-mediated G protein-dependent signaling. , Prosurvival effects of TRV027 and other βarr-biased AT 1 R ligands linked to the βarr-mediated signaling − and antagonism of G protein-mediated vasoconstriction and maladaptive phenotypes were suggested to be beneficial in treating myocardial fibrosis and cardiac hypertrophy. − …”

Section: Introductionmentioning

confidence: 99%

G Protein-Biased Agonists for Intracellular Angiotensin Receptors Promote Collagen Secretion in Myofibroblasts

Dallagnol,

Volkovich,

Chatenet

et al. 2023

ACS Chem. Biol.

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Photoactivatable ligands remain valuable tools to study the spatiotemporal aspects of cellular signaling. However, the synthesis, handling, and biological validation of such compounds remain challenging, especially when dealing with peptides. We report an optimized synthetic strategy, where laborious preparation of dimethoxy-nitrobenzyl-tyrosine building blocks was replaced by direct functionalization of amino acid side chains while peptides remained coupled to resin, reducing both preparation time and cost. Our caged peptides were designed to investigate cellular responses mediated by intracellular angiotensin II receptors (iATR) upon interaction with known biased and unbiased ligands. The pathophysiological roles of iATRs remain poorly understood, and we sought to develop ligands to explore this. Initial validation showed that our caged ligands undergo rapid photolysis and produced functionally active peptides upon UV exposure. We also show, for the first time, that different biased ligands (β-arrestin-vs G protein-biased analogues) evoked distinct responses when uncaged in adult rat myofibroblasts. Intracellularly targeted versions of Ang II (unbiased) or G protein-biased analogues (TRV055, TRV056) were more effective than β-arrestin-biased Ang II analogues (SI, TRV026, and TRV27) in inducing collagen secretion, suggesting a divergent role in regulating the fibrotic response.

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“…Heart failure (HF) is a multifaceted clinical syndrome characterized by significant morbidity and mortality. 1 The diagnostic criteria for HF include objective evidence of pulmonary or systemic congestion, as well as elevated levels of natriuretic peptides. In recent years, the incidence and prevalence of HF have increased continuously due to the growing aging population and presence of HF-related risk factors, such as hypertension, obesity, and diabetes.…”

Section: Introductionmentioning

confidence: 99%

Association between serum albumin to serum creatinine ratio and mortality risk in patients with heart failure

Li,

Xie,

Zeng

et al. 2023

Clinical Translational Sci

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The aim of this study was to investigate the association between serum albumin to serum creatinine ratio (sACR) and the prognosis of HF. In this single‐center prospective cohort study, a total of 2625 HF patients were enrolled between March 2012 and June 2017. All patients were divided into three groups according to the tertiles of sACR. Of 2625 patients, the mean age was 57.0±14.3. During a median follow‐up time of 23 months, 666 end point events occurred. Prognosis analysis indicated that the lowest sACR ratio was significantly associated with higher mortality risk of HF (HR= 1.920, 95% CI=1.585‐2.326; P< 0.001) when compared with the highest tertile. After adjusting for covariates including age, gender, diabetes, SBP, DBP, heart rate, total cholesterol, triglycerides, HDL‐C, LDL‐C, white blood cell count, hemoglobin, glycosylated hemoglobin and β‐blocer use, the HRs for mortality risk of HF was 1.513 (95% CI= 1.070‐2.139; P = 0.019). Subgroup analysis indicated that the mortality risk of HF statistically significantly reduced with the rise in sACR ratio in patients with no β‐blocker use, patients with serum creatine <97 μmol/L. However, stratification by age, sex, history of hypertension, diabetes and smoking, level of glycosylated hemoglobin and albumin have no obvious effect on the association between sACR ratio and the prognosis of HF. Additionally, patients with lower sACR displayed reduced left ventricular ejection fraction and increased left ventricular end‐diastolic diameter. The discriminant power of sACR alone and in combination with age, gender, SBP, heart rate and glycosylated hemoglobin were excellent with C statistic of 0.655 and 0.889, respectively. Lower sACR ratio was an independent risk factor for mortality risk of HF.

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β-Arrestin as a Therapeutic Target in Heart Failure

Cited by 11 publications

References 79 publications

A Common Variant of ARRB2 Promoter Region Associated with the Prognosis of Heart Failure

A Common Variant of ARRB2 Promoter Region Associated with the Prognosis of Heart Failure

G Protein-Biased Agonists for Intracellular Angiotensin Receptors Promote Collagen Secretion in Myofibroblasts

Association between serum albumin to serum creatinine ratio and mortality risk in patients with heart failure

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