The End of Heart Disease? Groundbreaking Experiment Stops Cholesterol Buildup

News Release : Apr 24, 2014
Ekaterina Pesheva - Johns Hopkins Medicine

Using mice and rabbits, Johns Hopkins scientists were able to successfully prevent the development of arteriosclerosis by halting a single molecule responsible for purging cholesterol in blood vessels.

(Baltimore, MD)—Working with mice and rabbits, Johns Hopkins scientists have found a way to block abnormal cholesterol production, transport and breakdown, successfully preventing the development of atherosclerosis, the main cause of heart attacks and strokes and the number-one cause of death among humans. The condition develops when fat builds inside blood vessels over time and renders them stiff, narrowed and hardened, greatly reducing their ability to feed oxygen-rich blood to the heart muscle and the brain. (Photo via humanlyexhausted.com)

In a series of experiments, described April 7 in the journal Circulation, the Johns Hopkins team says it identified and halted the action of a single molecular culprit responsible for a range of biological glitches that affect the body's ability to properly use, transport and purge itself of cholesterol — the fatty substance that accumulates inside vessels and fuels heart disease.

The offender, the researchers say, is a fat-and-sugar molecule called glycosphingolipid, or GSL, which resides in the membranes of all cells, and is mostly known for regulating cell growth. Results of the experiments, the scientists say, reveal that this very same molecule also regulates the way the body handles cholesterol.

The Johns Hopkins team used an existing man-made compound called D-PDMP to block the synthesis of the GSL molecule, and by doing so, prevented the development of heart disease in mice and rabbits fed a high-fat, cholesterol-laden diet. The findings reveal that D-PDMP appears to work by interfering with a constellation of genetic pathways that regulate fat metabolism on multiple fronts—from the way cells derive and absorb cholesterol from food, to the way cholesterol is transported to tissues and organs and is then broken down by the liver and excreted from the body. (Photo via DrLavanga.com)

"Current cholesterol-lowering medications tackle the problem on a single front — either by blocking cholesterol synthesis or by preventing the body from absorbing too much of it," says lead investigator Subroto Chatterjee, Ph.D., a cardio-metabolic expert at the Johns Hopkins Children's Center. "But atherosclerosis is a multi-factorial problem that requires hitting the abnormal cholesterol cycle at many points. By inhibiting the synthesis of GSL, we believe we have achieved exactly that."

Specifically, the experiments showed that treatment with D-PDMP led to:

• a drop in the animals' levels of so-called bad cholesterol or low-density lipoprotein, LDL;

• a drop in oxidized LDL, a particularly virulent form of fat that forms when LDL encounters free radicals. Oxidized LDL easily sticks to the walls of blood vessels, where it ignites inflammation, damaging the vessel walls and promoting the growth of fatty plaque;

• a surge in good cholesterol or high-density lipoprotein, HDL, known to counteract the effects of LDL by mopping it up; and

• a significant drop in triglycerides, another type of plaque-building fat.

The treatment also prevented fatty plaque and calcium deposits from building up inside the animals' vessels. These effects were observed in animals on a daily D-PDMP treatment even though they ate a diet made up of 20 percent triglycerides—the human equivalent of eating a greasy burger for breakfast, lunch and dinner. In addition, the researchers say, D-PDMP appears to precision-target the worst byproducts of aberrant cell growth signaling, such as oxidized LDL and the activity of certain chemicals that fuel vessel inflammation, without altering cell growth itself.

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