Related Experiment Video
Updated: Mar 10, 2026
Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity
Published on: July 10, 2019
Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure
Issam H Abu-Taha1, Jordi Heijman1, Hans-Jörg Hippe1
1From Institute of Experimental and Clinical Pharmacology and Toxicology, Mannheim Medical Faculty (I.H.A.-T., N.M.W., K.S., C.V., S.L., T.W.), and Department of Internal Medicine III (H.-J.H., N.M.W., M.M., B.M., H.-A.K., L.H.L., J.B.), Heidelberg University, Heidelberg-Mannheim, Germany; Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (I.H.A.-T., J.H., M.S., N.V., D.D.); Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Germany (A.E.-A., C.M.W., S.L.); Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Germany (A.E.-A.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Germany (V.O.N.); Department of Internal Medicine II, University of Regensburg, Germany (S.N.); Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Hungary (I.B., A.V.); Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.); and DZHK (German Center for Cardiovascular Research), Partner Site HD/MA, Heidelberg-Mannheim, Germany (B.M., H.A.K., C.V., J.B., T.W.). The current affiliation for H.-J.H. is the Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Kiel, Germany.
Insights
Nucleoside diphosphate kinase-C (NDPK-C) regulates cardiac contractility by modulating G protein signaling. This study reveals NDPK-C
Area of Science:
- Cardiovascular Biology
- Molecular Cell Biology
- Biochemistry
Background:
- Chronic heart failure (HF) involves altered G protein signaling and reduced cAMP formation.
- Nucleoside diphosphate kinases (NDPKs) are found at higher levels in the plasma membranes of HF patients, but their role is unclear.
- NDPK-C's specific function in cardiac cAMP production and contractility requires investigation.
Purpose of the Study:
- To investigate the role of Nucleoside Diphosphate Kinase-C (NDPK-C) in cardiac cyclic adenosine monophosphate (cAMP) formation.
- To determine NDPK-C's impact on cardiac contractility in heart failure.
- To elucidate the molecular mechanisms linking NDPK-C to G protein signaling in the heart.
Main Methods:
- Studied NDPK expression, G protein interaction, and localization using molecular biology techniques (PCR, Western blot, immunoprecipitation, immunocytochemistry).
- Quantified cAMP levels via immunoassays and Förster Resonance Energy Transfer (FRET).
- Assessed cardiac contractility in isolated cardiomyocytes and in vivo models.
Main Results:
- NDPK-C is crucial for NDPK-B/G protein complex formation and is upregulated in heart failure models.
- NDPK-C overexpression enhanced cAMP levels and contractility, while knockdown reduced them.
- In heart failure, NDPK-C shifts G protein activation from Gαs to Gαi2, decreasing cAMP and impairing contractility.
Conclusions:
- NDPK-C is essential for NDPK isoform and G protein interactions, acting as a key regulator of cardiac contractility.
- NDPK-C's switch in G protein activation contributes to reduced cAMP levels and contractile dysfunction in heart failure.
- NDPK-C represents a novel therapeutic target for managing heart failure-related signaling abnormalities.
Background:
Chronic heart failure (HF) is associated with altered signal transduction via β-adrenoceptors and G proteins and with reduced cAMP formation. Nucleoside diphosphate kinases (NDPKs) are enriched at the plasma membrane of patients with end-stage HF, but the functional consequences of this are largely unknown, particularly for NDPK-C. Here, we investigated the potential role of NDPK-C in cardiac cAMP formation and contractility.
Methods:
Real-time polymerase chain reaction, (far) Western blot, immunoprecipitation, and immunocytochemistry were used to study the expression, interaction with G proteins, and localization of NDPKs. cAMP levels were determined with immunoassays or fluorescent resonance energy transfer, and contractility was determined in cardiomyocytes (cell shortening) and in vivo (fractional shortening).
Results:
NDPK-C was essential for the formation of an NDPK-B/G protein complex. Protein and mRNA levels of NDPK-C were upregulated in end-stage human HF, in rats after long-term isoprenaline stimulation through osmotic minipumps, and after incubation of rat neonatal cardiomyocytes with isoprenaline. Isoprenaline also promoted translocation of NDPK-C to the plasma membrane. Overexpression of NDPK-C in cardiomyocytes increased cAMP levels and sensitized cardiomyocytes to isoprenaline-induced augmentation of contractility, whereas NDPK-C knockdown decreased cAMP levels. In vivo, depletion of NDPK-C in zebrafish embryos caused cardiac edema and ventricular dysfunction. NDPK-B knockout mice had unaltered NDPK-C expression but showed contractile dysfunction and exacerbated cardiac remodeling during long-term isoprenaline stimulation. In human end-stage HF, the complex formation between NDPK-C and Gαi2 was increased whereas the NDPK-C/Gαs interaction was decreased, producing a switch that may contribute to an NDPK-C-dependent cAMP reduction in HF.
Conclusions:
Our findings identify NDPK-C as an essential requirement for both the interaction between NDPK isoforms and between NDPK isoforms and G proteins. NDPK-C is a novel critical regulator of β-adrenoceptor/cAMP signaling and cardiac contractility. By switching from Gαs to Gαi2 activation, NDPK-C may contribute to lower cAMP levels and the related contractile dysfunction in HF.
Related Concept Videos
01:29Heart Failure II: Pathophysiology
01:30Cardiomyopathy II: Dilated Cardiomyopathy
02:34Inhibition of Cdk Activity
01:22Heart Failure Drugs: Diuretics
01:30Heart Failure V: Medical Management
01:15Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions