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

Abstract

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.

Keywords: NO-cGMP pathway; PDE-5; PDE-5 inhibitors; cGMP; hepatic encephalopathy; liver cirrhosis; liver fibrosis; nitric oxide; plasma markers; portal hypertension; sGC; sGC modulators.

Figure 1

The NO-cGMP pathway as the main regulator of sinusoidal and vascular tone in a healthy and cirrhotic liver (modified from Schaffner et al. (2018) [42] and Kreisel and Schaffner et al. (2020) [33]). (A) Regulation of sinusoidal tone in a healthy liver. In a healthy liver, an opposing zonation of sGC and PDE-5 may lead to high cGMP production in the peripheral parts of the hepatic lobule (high sGC), in which cGMP may exert its physiological function inside the sinusoids. Excess cGMP is possibly degraded by a high presence of PDE-5 (zone 3 hepatocytes) before entering extrahepatic vasculature. (B) Disturbed regulation of sinusoidal tone in liver cirrhosis. Altered expression of key enzymes in the NO-cGMP pathway (overexpression of eNOS and sGC and marked overexpression of PDE-5 in perisinusoidal cell, mainly activated HSCs) leads to reduced cGMP concentrations and sinusoidal constriction, increasing portal pressure. ↑ increased expression; ↑↑ markedly increased expression; cGMP ↓ decreased concentration. Red dots: PDE-5. Blue dots: sGC.

Figure 2

Targeting the NO-cGMP pathway for therapy of portal hypertension. Left side: Administration of PDE-5 inhibitors in liver cirrhosis leads to normalization of cGMP concentration and sinusoidal dilation. Portal pressure decreases and portal blood flow increases. Right side: Enhancing sGC activity in liver cirrhosis using an sGC stimulator or activator leads to increased cGMP levels and decreased sinusoidal tone. Portal pressure decreases and portal blood flow increases. ↑ increased expression; ↑↑ markedly increased expression; Ca ↓ decreased concentration; inhibition; stimulation/activation.

Figure 3

Immunostain for PDE-5 (red) of normal (A–D) and cirrhotic (E–H) human liver tissue. In normal control liver samples, PDE-5 is weakly expressed in hepatocytes around terminal hepatic venules (A). A higher intensity of staining is noted in perisinusoidal cells, especially in the perivenular region (B–D). Immunolabeling of cirrhotic liver tissue highlights the presence of PDE-5 in fibrous septa (E,C), in hepatocytes adjacent to veins (E,F), and in perisinusoidal cells scattered throughout the parenchyma.

Figure 4

Potential role of cGMP in hepatic encephalopathy. Hyperammonemia reduces the function of the glutamate-nitric oxide-cGMP pathway. Activation of NMDA receptors leads to increased intracellular calcium in the postsynaptic neuron. Calcium binds to calmodulin, which in turn activates function of calcium/calmodulin-dependent protein kinase II (CaMKII) by phosphorylation. CaMKII itself phosphorylates neuronal NO-synthase, reducing its activity and NO formation. This results in reduced synthesis of cGMP, leading to reduced learning ability. NMDA-receptor; ↑ increased expression; ↑↑ markedly increased expression; ↑ increased concentration; ↓ decreased concentration.

Figure 5

A model for peripheral vasodilation in progressed liver cirrhosis. In liver cirrhosis, NO is overexpressed in peripheral arterial blood vessels, while PDE-5 is decreased. This leads to high cGMP concentration and peripheral vasodilation.