Evidence map›Paper›PMID 32956449›Full record

ArticleCardiovascular research2021

Carvedilol induces biased β1 adrenergic receptor-nitric oxide synthase 3-cyclic guanylyl monophosphate signalling to promote cardiac contractility.

Qingtong Wang, Ying Wang, Toni M West, Yongming Liu, Gopireddy R Reddy, Federica Barbagallo, Bing Xu, Qian Shi, Bingqing Deng, Wei Wei and 1 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cardiovascular research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.

0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed
1.8field-weighted citation impact, top 15% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

25 citing papers in PubMed, 49 citations in OpenAlex.

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  19. New Therapeutics for Heart Failure: Focusing on cGMP Signaling.International journal of molecular sciences · 2023
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 5 institutions in 2 countries.

Qingtong WangThe Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
Ying WangDepartment of Pharmacology, University of California at Davis, Davis, 95616 CA, USA.
Toni M WestDepartment of Pharmacology, University of California at Davis, Davis, 95616 CA, USA.ORCID 0000-0001-7665-1860
Yongming LiuDepartment of Pharmacology, University of California at Davis, Davis, 95616 CA, USA.
Gopireddy R ReddyDepartment of Pharmacology, University of California at Davis, Davis, 95616 CA, USA.
Federica BarbagalloDepartment of Pharmacology, University of California at Davis, Davis, 95616 CA, USA.ORCID 0000-0002-2972-370X
Bing XuDepartment of Pharmacology, University of California at Davis, Davis, 95616 CA, USA.
Qian ShiDepartment of Pharmacology, University of California at Davis, Davis, 95616 CA, USA.
Bingqing DengDepartment of Pharmacology, University of California at Davis, Davis, 95616 CA, USA.
Wei WeiThe Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.ORCID 0000-0002-3117-9598
Yang K XiangDepartment of Pharmacology, University of California at Davis, Davis, 95616 CA, USA.ORCID 0000-0003-1786-9143
University of California, Davis · USMinistry of Education of the People's Republic of China · CNVA Northern California Health Care System · USShanghai University of Traditional Chinese Medicine · CNSun Yat-sen University · CN

Funding

Insulin Inhibition of beta-AR Signaling in the MyocardiumR01HL127764 · NHLBI · UNIVERSITY OF IOWA · PI ABEL, E DALE, XIANG, YANG K · 2015 to 2018
$2.4M
Molecular Regulation of cardiac adrenergic signalingR01HL147263 · NHLBI · UNIVERSITY OF CALIFORNIA AT DAVIS · PI XIANG, YANG K · 2019 to 2022
$1.7M
Cardiac Dysfunction in the Met Syndrome: Cross-talk between IR and bAR SignalingR01HL112413 · NHLBI · UNIVERSITY OF IOWA · PI ABEL, E DALE, XIANG, YANG K · 2015 to 2018
$1.6M
Novel mechanism on subpopulation-dependent biased GPCR signaling in neuronsR01GM129376 · NIGMS · UNIVERSITY OF CALIFORNIA AT DAVIS · PI XIANG, YANG K · 2018 to 2021
$1.6M
Molecular mechanisms of Insulin resistance under chronic stressI01BX002900 · VA · VA NORTHERN CALIFORNIA HEALTH CARE SYS · PI XIANG, YANG K · 2016 to 2021
–
American Heart AssociationAmerican Heart Association investigatorBLRD VA I01 BX002900NHLBI NIH HHS R01 HL112413NHLBI NIH HHS R01 HL127764NHLBI NIH HHS R01 HL147263NIGMS NIH HHS R01 GM129376United States Veteran's Administration Merit 01BX002900
6 · The paper itself

Abstract

aimsβ-blockers are widely used in therapy for heart failure and hypertension. β-blockers are also known to evoke additional diversified pharmacological and physiological effects in patients. We aim to characterize the underlying molecular signalling and effects on cardiac inotropy induced by β-blockers in animal hearts. METHODS AND

resultsWild-type mice fed high-fat diet (HFD) were treated with carvedilol, metoprolol, or vehicle and echocardiogram analysis was performed. Heart tissues were used for biochemical and histological analyses. Cardiomyocytes were isolated from normal and HFD mice and rats for analysis of adrenergic signalling, calcium handling, contraction, and western blot. Biosensors were used to measure β-blocker-induced cyclic guanosine monophosphate (cGMP) signal and protein kinase A activity in myocytes. Acute stimulation of myocytes with carvedilol promotes β1 adrenergic receptor (β1AR)- and protein kinase G (PKG)-dependent inotropic cardiac contractility with minimal increases in calcium amplitude. Carvedilol acts as a biased ligand to promote β1AR coupling to a Gi-PI3K-Akt-nitric oxide synthase 3 (NOS3) cascade and induces robust β1AR-cGMP-PKG signal. Deletion of NOS3 selectively blocks carvedilol, but not isoproterenol-induced β1AR-dependent cGMP signal and inotropic contractility. Moreover, therapy with carvedilol restores inotropic contractility and sensitizes cardiac adrenergic reserves in diabetic mice with minimal impact in calcium signal, as well as reduced cell apoptosis and hypertrophy in diabetic hearts.

conclusionThese observations present a novel β1AR-NOS3 signalling pathway to promote cardiac inotropy in the heart, indicating that this signalling paradigm may be targeted in therapy of heart diseases with reduced ejection fraction.

Indexed as

Adrenergic alpha-1 Receptor AntagonistsAnimalsCardiotonic AgentsCarvedilolCells, CulturedCyclic GMPCyclic GMP-Dependent Protein KinasesDisease Models, AnimalHeart DiseasesMaleMiceMice, Inbred C57BLMice, KnockoutMyocardial ContractionMyocytes, CardiacNitric Oxide Synthase Type IIIAdrb1 protein, mouseAdrenergic alpha-1 Receptor AntagonistsCardiotonic AgentsCarvedilolCyclic GMPCyclic GMP-Dependent Protein KinasesNitric Oxide Synthase Type IIINos3 protein, mouseReceptors, Adrenergic, beta-1CarvedilolContractilityCyclic guanosine monophosphateHeart dysfunctionβ adrenergic receptor

Identifiers

PMID32956449
PMCPMC8502477
OpenAlexW3087673775

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.