HQ Team
November 24, 2022: High cholesterol levels are generally treated with statins and sometimes with PCSK-9, a protein inhibitor that lowers cholesterol. Now scientists at University Hospitals (UH) and Case Western Reserve University School of Medicine, US, have developed an orally administered small-molecule drug that reduces PCSK9 levels and lowers cholesterol in animal models by 70%.
The research may also impact cancer treatments.
PCSK-9 is a type of laboratory-made protein that works by inhibiting protein made in the liver. Research has shown that people with low levels of this protein tend to have low cholesterol and a lower risk of heart disease. PCSK-9 inhibitors are not commonly used as they need to be injected.
“Cholesterol lowering is one of the most important therapies we have to prolong life and protect people from heart disease, which is still the number one cause of morbidity and mortality in the Western world,” said senior author Jonathan S. Stamler, Professor at UH and Case Western Reserve School of Medicine.
“Statins only lower cholesterol so far. This is a drug class that we think would represent a new way to lower cholesterol, a new way to hit PCSK9,” Stamler said.
PCSK9 in the bloodstream controls the number of LDL receptors by marking them for degradation. LDL receptors sit on the surface of liver cells and remove cholesterol from the blood, thereby lowering serum levels.
Nitric oxide is a molecule that is known to prevent heart attacks by dilating blood vessels. The researchers used a nitric oxide-derived molecule’s ability to lower cholesterol by inhibiting PCSK-9 enzymes in cell and mouse models. Mice treated with the drug display a 70% reduction in LDL “bad” cholesterol.
“Our drug works by increasing a molecule called nitric oxide, which is known to prevent heart attacks by dilating blood vessels. We show that nitric oxide inactivates PCSK9, thereby increasing removal of bad cholesterol,” said Dr Stamler
In addition to impacting the field of cholesterol metabolism, the findings may impact patients with cancer, as emerging evidence suggests targeting PCSK9 can improve the efficacy of cancer immunotherapies, the researchers said.
“PCSK9 not only targets LDL receptors for degradation, it also mediates the degradation of MHC 1 on lymphocytes, which is used for recognition of cancer cells,” said Stamler.
“PCSK9 is effectively preventing your lymphocytes from recognising cancer cells. So, if you inhibit PCSK9, you can boost the body’s cancer surveillance.” He added.
The study was published in Cell Reports.
