High levels of LDL cholesterol increase your risk of cardiovascular disease. This is because high levels of LDL cholesterol cause plaque to form inside your arteries, narrowing them and reducing oxygen flow to your heart muscle.
Researchers at University Hospitals and Case Western Reserve University have discovered a small molecule drug that significantly lowers blood cholesterol levels in mice.
PCSK9 inhibitors are the second most commonly prescribed medications for lowering cholesterol after statins. They work by blocking the action of a protein called proprotein convertase subtilisin/kexin 9 (PCSK9), which normally removes cholesterol from the body. Because this drug requires injections, it can be a barrier to its use for some patients.
Researchers at University Hospitals and Case Western Reserve University School of Medicine have discovered a new way to treat high cholesterol and potentially prevent heart disease. Their research shows that a small molecule drug called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor works by blocking the enzyme responsible for removing LDL cholesterol from blood vessels. This finding represents a new approach to treating high cholesterol and may also have implications for cancer treatments.
“Cholesterol lowering is one of the most important therapies we have to prolong life and protect people from heart disease, which is still the leading cause of death worldwide,” says Dr. Jonathan S. Stamler, Senior Author, Harrington Discovery Institute at University Hospitals Cleveland Medical Center, and Professor of Medicine and Biochemistry at 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.”
Cholesterol regulation is central to regulating how much cholesterol is removed from the body. The LDL receptor sits at the surface of liver cells and removes cholesterol from the blood, thereby lowering serum levels. In the bloodstream, PCSK9 binds to the LDL receptor and marks it for degradation. Agents that inhibit PCSK9 increase the number of LDL receptors that remove cholesterol.
A new compound discovered by researchers at Johns Hopkins University School of Medicine can lower bad cholesterol levels by inhibiting the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9), according to research published today in Cell Metabolism. The findings suggest that this class of drugs may prove effective in treating high cholesterol and cardiovascular disease.
Cancer Prevention Beyond Cholesterol
A study published today in Nature Medicine shows how blocking a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9) improves the effectiveness of immune therapies used against cancers.
“PCSK9 not only targets LDL receptors for degradation, but it also mediates the degradation of MHC 1 on lymphocytes, which is used for recognition of cancer cells,” says Stamler. “PCSK9 is effectively preventing your lymphocytes from recognizing cancer cells. So, if you inhibit PCSK9, you can boost the body’s cancer surveillance.” There may be an opportunity one day to apply these new drugs to that need.”
Reference: “A multienzyme S-nitrosylation cascade regulates cholesterol homeostasis” by Colin T. Stomberski, Nicholas M. Venetos, Hua-Lin Zhou, Zhaoxia Qian, Bryce R. Collison, Seth J. Field, Richard T. Premont and Jonathan S. Stamler, 25 October 2022, Cell Reports.