Cardiac βarrestin2 Improves Contractility and Adverse Remodeling in Heart Failure, But Is Underexpressed in Humans

McCrink, Katie A; Maning, Jennifer; Vu, Angela; Jafferjee, Malika; Marrero, Christine; Brill, Ava; Bathgate-Siryk, Ashley; Dabul, Samalia; Koch, Walter J.; Lymperopoulos, Anastasios

doi:10.1016/j.jacc.2017.10.008

Cited by 20 publications

(19 citation statements)

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“…Finally, the third and therapeutically salient unanswered question pertains to the expression levels of the cardiac β-arrestins in the failing human heart. Although β-arrestin-2 protein is significantly under-expressed, compared to β-arrestin-1, in the non-failing human adult myocardium[22,64], which makes cardiac-specific β-arrestin-2 gene transfer an enticing approach for heart failure treatment, its protein levels (and if they change) in human heart failure remain unknown. However, given that it is significantly expressed at the mRNA level, and in fact at levels comparable to those of β-arrestin-1 mRNA, in the failing human heart[64], it is quite plausible that it might be upregulated at the protein level, similarly to GRK2, as a homeostatic mechanism of the failing human myocardium to confer cardioprotection.…”

Section: Resultsmentioning

confidence: 99%

“…β-arrestin-2 also increases cardiac function indirectly by leaving the β 1 AR-stimulated cAMP-dependent pro-contractile signaling intact ( i.e ., not desensitizing it) in cardiac myocytes in vitro and in post-MI heart failure mice in vivo (Figure 1)[20]. Importantly, these effects are not shared by the vastly more abundant in the human heart β-arrestin-1[22].…”

Section: Functional Differences Between the Two Beta Arrestins In Carmentioning

confidence: 99%

“…Second, the compounds might have not been completely β-arrestin-“biased” ( i.e ., maybe they had some weak, residual activity towards certain G-proteins). One intriguing possibility is that, due to the significantly lower abundance of the cardioprotective β-arrestin-2, compared to the cardio-toxic β-arrestin-1, in human cardiomyocytes[22], these β-arrestin-“biased” compounds stimulated, in reality, β-arrestin-1 instead of β-arrestin-2 in the patients` hearts and that’s why their clinical outcomes were not the desired ones. Finally, it is very likely that these compounds stimulated the AT 1 R only in cardiac fibroblasts, which would preclude any clinical benefit for ADHF patients.…”

Section: Functional Differences Between the Two Beta-arrestins In Carmentioning

confidence: 99%

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Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β arrestins in the heart

Lymperopoulos

Wertz

Pollard

et al. 2019

WJC

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The two ubiquitous, outside the retina, G protein-coupled receptor (GPCR) adapter proteins, β-arrestin-1 and -2 (also known as arrestin-2 and -3, respectively), have three major functions in cells: GPCR desensitization, i.e ., receptor decoupling from G-proteins; GPCR internalization via clathrin-coated pits; and signal transduction independently of or in parallel to G-proteins. Both β-arrestins are expressed in the heart and regulate a large number of cardiac GPCRs. The latter constitute the single most commonly targeted receptor class by Food and Drug Administration-approved cardiovascular drugs, with about one-third of all currently used in the clinic medications affecting GPCR function. Since β-arrestin-1 and -2 play important roles in signaling and function of several GPCRs, in particular of adrenergic receptors and angiotensin II type 1 receptors, in cardiac myocytes, they have been a major focus of cardiac biology research in recent years. Perhaps the most significant realization coming out of their studies is that these two GPCR adapter proteins, initially thought of as functionally interchangeable, actually exert diametrically opposite effects in the mammalian myocardium. Specifically, the most abundant of the two β-arrestin-1 exerts overall detrimental effects on the heart, such as negative inotropy and promotion of adverse remodeling post-myocardial infarction (MI). In contrast, β-arrestin-2 is overall beneficial for the myocardium, as it has anti-apoptotic and anti-inflammatory effects that result in attenuation of post-MI adverse remodeling, while promoting cardiac contractile function. Thus, design of novel cardiac GPCR ligands that preferentially activate β-arrestin-2 over β-arrestin-1 has the potential of generating novel cardiovascular therapeutics for heart failure and other heart diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Functional Differences Between the Two Beta Arrestins In Carmentioning

confidence: 99%

Section: Functional Differences Between the Two Beta-arrestins In Carmentioning

confidence: 99%

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Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β arrestins in the heart

Lymperopoulos

Wertz

Pollard

et al. 2019

WJC

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“…; McCrink et al . ,b). It has been reported that in normal physiological conditions, βarr1 and 2 are differentially expressed in rat brain regions (Attramadal et al .…”

Section: Discussionmentioning

confidence: 99%

Role of βarrestin1 in AT₁R‐mediated mitogen‐activated protein kinase activation in Wistar and SHR brainstem astrocytes

Negussie

Lymperopoulos

Clark

2018

Journal of Neurochemistry

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barrestin (barr)-1 and -2 are ubiquitously (outside the retina) expressed G-protein-coupled receptor adapter proteins. They uncouple G-protein-coupled receptors from G proteins, internalize the receptor, and subsequently initiate their own wave of signaling independently of G proteins. Angiotensin (Ang) II type 1 receptor (AT 1 R) is a well-established example of a receptor signaling through barrs. Despite the pivotal role of brain AT 1 Rs in the regulation of blood pressure, the involvement of barr-dependent signaling, mediated by AT 1 Rs is not well studied. Particularly, in brain astrocytes very little is known about the effects of barrs in AT 1 R signaling. Herein, we utilized a combination of pharmacological and gene manipulation approaches to investigate the role of barrs in AT 1 R-mediated signaling in isolated brainstem astrocytes from spontaneously hypertensive rats (SHRs) and Wistar rats. We observed that barr1 is the predominant arrestin isoform at the protein level in these cells. Its expression was down-regulated in SHR astrocytes compared to Wistar rat astrocytes. Ang II, contrary to observations in SHR astrocytes where it had no effect, upregulates barr1 protein in Wistar rat astrocytes. We observed differential involvement of barr1 in MAPK activation in brainstem astrocytes of SHR versus Wistar rats. The barr-biased agonist peptide [Sar 1 , Il 4 , Il8] Ang-II (SII), induced AT 1 Rmediated ERK and p38 activation in Wistar rat astrocytes. SII had no effect on ERK and p38 activation in SHRs brainstem astrocytes. Our results indicate, reduced involvement of barr1 in dampening Ang II-induced MAPKs activation and diminished barr1-mediated ERK and p38 activation in SHR brainstem astrocytes. These findings might be mechanistically related to the development of the brain renin-angiotensinaldosterone system hyperactivity, which leads to pathogenesis of the hypertensive state of the SHR model.

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“…1) [141]. Importantly, these effects are not shared by the vastly more abundant in the human heart β–arrestin1 [142].…”

Section: Cardiac Cell Type‐specific Ans Receptor Signaling: Emerging Insights and Paradigmsmentioning

confidence: 99%

Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe

et al. 2021

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The two branches of the autonomic nervous system (ANS), adrenergic and cholinergic, exert a multitude of effects on the human myocardium thanks to the activation of distinct G protein-coupled receptors (GPCRs) expressed on the plasma membranes of cardiac myocytes, cardiac fibroblasts, and coronary vascular endothelial cells. Norepinephrine (NE)/epinephrine (Epi) and acetylcholine (ACh) are released from cardiac ANS terminals and mediate the biological actions of the ANS on the heart via stimulation of cardiac adrenergic or muscarinic receptors, respectively. In addition, several other neurotransmitters/hormones act as facilitators of ANS neurotransmission in the heart, taking part in the so-called nonadrenergic noncholinergic (NANC) part of the ANS's control of cardiac function. These NANC mediators also use several different cell membrane-residing GPCRs to exert their effects in the myocardium. Cardiac ANS dysfunction and an imbalance between the activities of its two branches underlie a variety of cardiovascular diseases, from heart failure and hypertension to coronary artery disease, myocardial ischemia, and arrhythmias. In this review, we present the main well-established signaling modalities used by cardiac autonomic GPCRs, including receptors for salient NANC mediators, and we also highlight the latest developments pertaining to cardiac cell type-specific signal transduction, resulting in cell type-specific cardiac effects of each of these autonomic receptors.

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Cardiac βarrestin2 Improves Contractility and Adverse Remodeling in Heart Failure, But Is Underexpressed in Humans

Cited by 20 publications

References 3 publications

Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β arrestins in the heart

Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β arrestins in the heart

Role of βarrestin1 in AT₁R‐mediated mitogen‐activated protein kinase activation in Wistar and SHR brainstem astrocytes

Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe

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Cardiac βarrestin2 Improves Contractility and Adverse Remodeling in Heart Failure, But Is Underexpressed in Humans

Cited by 20 publications

References 3 publications

Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β arrestins in the heart

Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β arrestins in the heart

Role of βarrestin1 in AT1R‐mediated mitogen‐activated protein kinase activation in Wistar and SHR brainstem astrocytes

Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe

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Product

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Role of βarrestin1 in AT₁R‐mediated mitogen‐activated protein kinase activation in Wistar and SHR brainstem astrocytes