Next Article in Journal
Prognostic and Predictive Biomarkers in Gliomas
Next Article in Special Issue
Clinical Implication of Phosphodiesterase-4-Inhibition
Previous Article in Journal
Adenylate Kinase 4—A Key Regulator of Proliferation and Metabolic Shift in Human Pulmonary Arterial Smooth Muscle Cells via Akt and HIF-1α Signaling Pathways
Previous Article in Special Issue
Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016
Review

Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications

1
Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
2
Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
3
Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany
4
Institute of Forensic Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
5
Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
*
Author to whom correspondence should be addressed.
Shared first authorship of Wolfgang Kreisel and Adhara Lazaro.
Academic Editors: Mauro Giorgi, Manuela Pellegrini and Mara Massimi
Int. J. Mol. Sci. 2021, 22(19), 10372; https://doi.org/10.3390/ijms221910372
Received: 14 September 2021 / Revised: 20 September 2021 / Accepted: 21 September 2021 / Published: 26 September 2021
(This article belongs to the Special Issue Role of Phosphodiesterase in Biology and Pathology 2.0)
The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the “NO-paradox”, referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies. View Full-Text
Keywords: liver cirrhosis; liver fibrosis; portal hypertension; NO-cGMP pathway; sGC; PDE-5; cGMP; nitric oxide; sGC modulators; PDE-5 inhibitors; hepatic encephalopathy; plasma markers liver cirrhosis; liver fibrosis; portal hypertension; NO-cGMP pathway; sGC; PDE-5; cGMP; nitric oxide; sGC modulators; PDE-5 inhibitors; hepatic encephalopathy; plasma markers
Show Figures

Figure 1

MDPI and ACS Style

Kreisel, W.; Lazaro, A.; Trebicka, J.; Grosse Perdekamp, M.; Schmitt-Graeff, A.; Deibert, P. Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications. Int. J. Mol. Sci. 2021, 22, 10372. https://doi.org/10.3390/ijms221910372

AMA Style

Kreisel W, Lazaro A, Trebicka J, Grosse Perdekamp M, Schmitt-Graeff A, Deibert P. Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications. International Journal of Molecular Sciences. 2021; 22(19):10372. https://doi.org/10.3390/ijms221910372

Chicago/Turabian Style

Kreisel, Wolfgang, Adhara Lazaro, Jonel Trebicka, Markus Grosse Perdekamp, Annette Schmitt-Graeff, and Peter Deibert. 2021. "Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications" International Journal of Molecular Sciences 22, no. 19: 10372. https://doi.org/10.3390/ijms221910372

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop