Journal
CARDIOVASCULAR RESEARCH
Volume 117, Issue 10, Pages 2237-2251Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvaa266
Keywords
Carvedilol; Cyclic guanosine monophosphate; Heart dysfunction; beta adrenergic receptor; Contractility
Categories
Funding
- National Institute of Health [R01-HL127764, R01-HL112413]
- United States Veteran's Administration Merit grant [01BX002900]
- American Heart Association
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The study investigated the molecular signaling and effects of beta-blockers on cardiac inotropy in animal hearts. The results showed that carvedilol, a beta-blocker, can promote cardiac contractility through a specific signaling pathway, restoring heart function in diabetic mice and reducing cell apoptosis and hypertrophy in diabetic hearts.
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.
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