Under Pressure: Understanding The Causes Of Portal Hypertension After Liver Injury

Cirrhosis is a condition that results from liver injury, whether it be caused by alcohol, hepatitis or fatty liver diseases. Cirrhosis is a condition in which the liver attempts self-healing. It can also cause portal hypertension, an increase in blood pressure. Portal hypertension is an untreatable, often fatal, consequence of liver injury.

In the recent study, Don C. Rockey, M.D., chair of the Department of Medicine at MUSC, and his colleagues at MUSC and Duke University studied the proteins underlying portal hypertension and identified a potential therapeutic target.

Rockey said, "From our perspective, I think this represents an exciting potential avenue of novel treatment for portal hypertension patients." "We've uncovered a new mechanism that explains why patients have the disease and we think that interrupting this is a novel way to treat it."

Following liver injury, the activity of eNOS is reduced. This causes a decrease in eNOS activity, which leads to decreased NO production, and increases in portal pressure. This article focuses on caveolin-1 (CAV1), and G-protein-coupled kinase-2(GRK2) proteins. The function of this complex in regulating NO production is not well understood. This article will attempt to answer this question.

Songling Liu MD, is the lead author of this study. "We found that inhibiting GRK2 phosphorylation or CAV1 compromises complex formation and reduces eNOS activation."
GAMING

Liu and colleagues compared normal and injured livers. They found that total levels of proteins in this process were the same. However, their localization within cells, ability to form complexes and ability to elicit no production were significantly impaired in injured livers.

This article provides a more detailed picture of proteins involved with NO production and their function in response to injury. CAV1 is modified by phosphorylation upon injury. This modification increases the ability for CAV1 to form a complex with GRK2. The CAV1/GRK2 Complex sequesters eNOS and hinders its ability to synthesize it.

The knowledge gained from focusing on the changes in protein function following injury may provide a platform for the development of novel treatment options for portal hypertension.

Rockey said, "If we could dissociate CAV1 in injury, then theoretically we would see an increase NO production and that we could treat patients with."

While seeing a new treatment for portal hypertension in the clinic is several years away, compounds that block the ability of GRK2 to interact with CAV1 and eNOS could potentially provide the first new treatment in more than forty years. Portal hypertension, which is a disease that affects the liver, could be treated with drugs that target the portal venous systems. This would prevent side effects and systemic complications.