From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure

Bernardo, Bianca C.; Blaxall, Burns C.

doi:10.1016/j.hlc.2016.01.002

Cited by 15 publications

(8 citation statements)

References 89 publications

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“…Interestingly, as in the present study, the effects of AGS3 can be, at least in acute kidney injury, inhibited by addition of the G-protein β/γ signaling inhibitor gallein (Regner et al, 2011). In fact, there has been an emerging interest in targeting G-protein β/γ signaling for clinical intervention in multiple diseases such as heart failure or acute kidney injury (Lin and Smrcka, 2011;White et al, 2014;Bernardo and Blaxall, 2016). Especially as gallein and its derivatives do not cause obvious side effects in mice (Lin and Smrcka, 2011).…”

Section: Discussionsupporting

confidence: 65%

Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney

2018

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The development of the kidney relies on the establishment and maintenance of a precise tubular diameter of its functional units, the nephrons. This process is disrupted in polycystic kidney disease (PKD), resulting in dilations of the nephron and renal cyst formation. In the course of exploring G-protein-coupled signaling in the pronephric kidney, we discovered that loss of the G-protein α subunit, Gnas, results in a PKD phenotype. Polycystin 1, one of the genes mutated in human PKD, encodes a protein resembling a G-protein-coupled receptor. Furthermore, deletion of the G-protein-binding domain present in the intracellular C terminus of polycystin 1 impacts functionality. A comprehensive analysis of all the G-protein α subunits expressed in the pronephric kidney demonstrates that polycystin 1 recruits a select subset of G-protein α subunits and that their knockdown - as in the case of Gnas - results in a PKD phenotype. Mechanistically, the phenotype is caused by increased endogenous G-protein β/γ signaling and can be reversed by pharmacological inhibitors as well as knocking down Gnb1. Together, our data support the hypothesis that G proteins are recruited to the intracellular domain of PKD1 and that this interaction is crucial for its function in the kidney.

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Section: Discussionsupporting

confidence: 65%

Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney

2018

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“…fluvoxamine were demonstrated on ischemia-reperfusion injury, which is in line with the observation that serotonin is activated during ischemia-reperfusion and triggers contractile dysfunction and pathological apoptosis [44, 45]. Paroxetine was discussed a new pharmacological agents for heart failure therapy [46] (see Fig. 2).…”

Section: In Patients With Cardiovascular Disorders Use Serotonin Reupmentioning

confidence: 64%

Depression in the Context of Medical Disorders: New Pharmacological Pathways Revisited

Lang¹,

Walter²

2017

Neurosignals

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The depressive state has been characterised as one of elevated inflammation, changed cardiovascular parameters and a deranged metabolic situation all of which holds promise for a better understanding and handling of treatment-resistance in affective disorders as well as for future developments in treatment algorithms. In this context several biomarkers are differentially regulated by antidepressant treatment and connected to metabolic, inflammatory, cardiovascular and apoptotic components of the pathophysiology, i.e. adiponectin, apolipoprotein-B, B-type natriuretic peptide, cortisol, CRP, cysteine, homocysteine, fibrinogen, adiponectin, BMI, glycated hemoglobin A1c, leptin, interferon-gamma, high-density lipoprotein, interleukin interleukin-1alpha, -1beta, -2, -4, -5, -6, -8, -10, -12, -13, -17, insulin-like growth factor-1, low-density lipoprotein, myeloperoxidase, osteoprotegerin, tumour necrosis factor alpha, troponins, triglycerides etc. In this context antidepressants exert different modulatory effects on the outcome, incidence and mortality concerning several severe disorders, i.e. cancer, diabetes, stroke, inflammation, stroke and cardiovascular risk. Vice versa different drugs used in the treatment of these disorders have a favourable effect in depressive states, e.g. statins, aspirine, NSAIDs, pioglitazone, celecoxib, peroxisome proliferator-activated receptor-gamma agonists and minocycline. In this review, actions of different antidepressant treatment strategies on cancer, stroke, diabetes and cardiovascular disorders are shown and the influence on the outcome of the disorders is differentially discussed. In conclusion a hypothetic model for the implication of actual findings in everyday clinical practice is proposed. In this context personalized treatment could be used to tailor treatment to specific individuals according to their clinical endophenotypes. Moreover a potential target for the development of novel intervention strategies might be used.

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“…Another potential strategy to interdict Gβγ-GRK2 pathologic signaling is targeting Gβγ subunit and inhibiting its protein-protein interactions [5] and [66]. Hence, Bonacci et al in 2006 performed a virtual screening of 1990 compounds from the National Cancer Institute (NCI) chemical library to identify small molecules capable of binding Gβγ protein interaction domain mentioned above [79].…”

Section: Gβγ-grk2 Signaling Manipulation As a Strategy To Treat Camentioning

confidence: 99%

“…About 5.7 million adults in the United States are affected by this debilitating disease [3]; HF treatment costs the nation an estimated $30.7 billion each year [4]. Notwithstanding significant advances in HF treatment and management realized with β-adrenergic receptor (β-AR) blockers, angiotensin receptor blockers, angiotensin converting enzyme (ACE) inhibitors, aldosterone inhibitors, and diuretics, conventional pharmacological therapies only impede the progression and death due to HF, but do not cure it causatively [5]. Taking into consideration the steady growth of aging and diabetic populations, deeper understanding of the molecular and cellular processes that contribute to the disease pathogenesis, along with development of innovative therapeutic strategies allowing the causative cure of HF, are indispensable.…”

Section: Introductionmentioning

confidence: 99%

Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies

Rudomanova

Blaxall

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The pathologic crosstalk between the heart and kidney is known as cardiorenal syndrome (CRS). While the specific mechanisms underlying this crosstalk remain poorly understood, CRS is associated with exacerbated dysfunction of either or both organs and reduced survival. Maladaptive fibrotic remodeling is a key component of both heart and kidney failure pathogenesis and progression. G-protein coupled receptor (GPCR) signaling is a crucial regulator of cardiovascular and renal function. Chronic/pathologic GPCR signaling elicits the interaction of the G-protein Gβγ subunit with GPCR kinase 2 (GRK2), targeting the receptor for internalization, scaffolding to pathologic signals, and receptor degradation. Targeting this pathologic Gβγ-GRK2 interaction has been suggested as a possible strategy for the treatment of HF. In the current review, we discuss recent updates in understanding the role of GPCR-Gβγ-GRK2 signaling as a crucial mediator of maladaptive organ remodeling detected in HF and kidney dysfunction, with specific attention to small molecule-mediated inhibition of pathologic Gβγ-GRK2 interactions. Further, we explore the potential of GPCR-Gβγ-GRK2 signaling as a possible therapeutic target for cardiorenal pathologies.

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From Bench to Bedside: New Approaches to Therapeutic Discovery for Heart Failure

Cited by 15 publications

References 89 publications

Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney

Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney

Depression in the Context of Medical Disorders: New Pharmacological Pathways Revisited

Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies

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