Journal article
Carvedilol induces biased beta(1) adrenergic receptor-nitric oxide synthase 3-cyclic guanylyl monophosphate signalling to promote cardiac contractility
Cardiovascular research, Vol.117(10), pp.2237-2251
09/01/2021
DOI: 10.1093/cvr/cvaa266
PMCID: PMC8502477
PMID: 32956449
Abstract
Aims beta-blockers are widely used in therapy for heart failure and hypertension. beta-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 beta-blockers in animal hearts.
Methods and results Wild-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 beta-blocker-induced cyclic guanosine monophosphate (cGMP) signal and protein kinase A activity in myocytes. Acute stimulation of myocytes with carvedilol promotes beta(1) adrenergic receptor (beta(1)AR)- and protein kinase G (PKG)-dependent inotropic cardiac contractility with minimal increases in calcium amplitude. Carvedilol acts as a biased ligand to promote beta(1)AR coupling to a G(i)-PI3K-Akt-nitric oxide synthase 3 (NOS3) cascade and induces robust beta(1)AR-cGMP-PKG signal. Deletion of NOS3 selectively blocks carvedilol, but not isoproterenol-induced beta(1)AR-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.
Conclusion These observations present a novel beta(1)AR-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.
Details
- Title: Subtitle
- Carvedilol induces biased beta(1) adrenergic receptor-nitric oxide synthase 3-cyclic guanylyl monophosphate signalling to promote cardiac contractility
- Creators
- Qingtong Wang - University of California, DavisYing Wang - University of California, DavisToni M. West - University of California, DavisYongming Liu - University of California, DavisGopireddy R. Reddy - University of California, DavisFederica Barbagallo - University of California, DavisBing Xu - University of California, DavisQian Shi - University of California, DavisBingqing Deng - University of California, DavisWei Wei - Anhui Medical UniversityYang K. Xiang - University of California, Davis
- Resource Type
- Journal article
- Publication Details
- Cardiovascular research, Vol.117(10), pp.2237-2251
- DOI
- 10.1093/cvr/cvaa266
- PMID
- 32956449
- PMCID
- PMC8502477
- NLM abbreviation
- Cardiovasc Res
- ISSN
- 0008-6363
- eISSN
- 1755-3245
- Publisher
- Oxford Univ Press
- Number of pages
- 15
- Grant note
- 01BX002900 / United States Veteran's Administration Merit grant American Heart Association R01-HL127764; R01-HL112413 / National Institute of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 09/01/2021
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359577202771
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