August 21, 2014

Major grant spurs deeper look into ‘good cholesterol’

In some cases, HDL, the “good cholesterol,” may not function properly and may actually accelerate atherosclerosis.

From left, Sean Davies, Ph.D., Kasey Vickers, Ph.D., MacRae F. Linton, M.D., L. Jackson Roberts II, M.D., and Valentina Kon, M.D., discuss recent findings about high-density lipoprotein (HDL) on a “clear board.” They are part of a major program project grant funded by the NIH to explore the impact of HDL “dysfunction” on heart disease. (photo by Joe Howell)

High-density lipoprotein (HDL) is known as “good cholesterol” because elevated levels protect against heart attacks and atherosclerosis (plaque build-up). However, in some cases HDL may not function properly and may actually accelerate the disease.

MacRae Linton, M.D., who directs the Vanderbilt Lipid Clinic, is principal investigator of a five-year, $11.8 million federal grant to find out why.

“This is a hot area of debate,” said Linton, the Dr. Stephen Schillig Jr. and Mary Schillig Professor of Medicine and Professor of Pharmacology. But “there’s a lot of evidence to support the idea that HDL cholesterol levels don’t tell the whole story and HDL function is important.”

Program project grant HL116263, awarded this summer by the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH), focuses on three disorders with elevated heart disease risk — rheumatoid arthritis, chronic kidney disease, and familial hypercholesterolemia (FH).

FH is a genetic disorder characterized by high levels of low-density lipoprotein (LDL), the “bad” form of cholesterol.

In addition to Linton, grant subprojects are led by L. Jackson Roberts II, M.D., and Valentina Kon, M.D., working with Sean Davies, Ph.D., C. Michael Stein, M.B.Ch.B., Kasey Vickers, Ph.D., Patricia Yancey, Ph.D., and colleagues.

Linton said that while statins, which lower LDL levels, are the most effective current way to prevent heart attacks, they don’t prevent them all. HDL “dysfunction” may contribute to this “residual” risk. In fact, more heart attacks are associated with low HDL levels than with high LDL levels.

HDL normally takes excess cholesterol from the tissues and delivers it to the liver to be disposed of, an important protective function called “reverse cholesterol transport.”

But HDL also has anti-inflammatory, anti-oxidant, and anti-thrombotic functions, Linton said. HDL dysfunction in any of these areas may help explain why some people have heart attacks and strokes even though their LDL levels are normal.

“If you could identify the mechanisms causing HDL dysfunction,” he said, “you might be able to go to the next step and design new therapies to prevent heart attacks.”

It turns out that HDL carries a lot of different biologically active substances in the blood. One of the major ideas being explored is that the cargo carried by HDL influences its function.

Roberts, the William Stokes Professor of Experimental Therapeutics and professor of Medicine and Pharmacology, is leading a study of isoprostanes, chemical markers of oxidative stress that he and the late Jason Morrow, M.D., discovered in 1990.

Isoprostanes are formed when free radicals — highly reactive molecules derived from oxygen — attack lipids in cell membranes.

HDLs are major carriers of isoprostanes (markers of oxidative stress) in the blood. Isoprostanes are produced in parallel with another family of highly reactive compounds, isolevuglandins, also known as isoketals, which may damage HDLs. Roberts and Davies, assistant professor of Pharmacology, are investigating whether isoprostanes and isolevuglandins directly cause HDL dysfunction.

With Stein, the Dan May Professor of Medicine and professor of Pharmacology, they also will explore his recent observations that patients with rheumatoid arthritis who had high HDL levels had increased atherosclerosis if they also had high isoprostane levels.

These patients have increased inflammation and risk of early heart disease, but the reasons for this are poorly understood.

Kon, professor of Pediatrics, is exploring a possible link between HDL function and increased cardiovascular risk in patients with chronic kidney disease. Kon and co-workers recently reported that HDL from end-stage renal disease patients on hemodialysis was dramatically less effective than normal HDL in accepting cholesterol from macrophages for disposal.

“Patients on dialysis (are) really the only group of high-risk patients where statins have not been able to show a benefit in terms of reducing cardiovascular events,” Linton said. “We think dysfunctional HDL may be an important part of their increased risk.”

Linton is examining factors besides high LDL that may increase heart disease risk in patients with FH. The anti-inflammatory function of HDL seems to be impaired in patients with the most severe form of the disease. “If anything, their HDL seems to be pro-inflammatory,” he said.

With Vickers, assistant professor of Medicine and of Molecular Physiology and Biophysics, Linton also is investigating the possible role of microRNA in HDL dysfunction.

MicroRNAs, which regulate gene expression, are transported in blood by HDLs, Vickers and his colleagues reported in 2011 when he was an NIH postdoctoral fellow.

Patients with FH have “strikingly different” patterns of microRNAs in their HDLs compared to the general population, Linton noted. A major goal of the program project grant is to investigate the role of microRNAs on HDL function in FH as well as chronic kidney disease and rheumatoid arthritis.

The grant also supports core labs essential for the research. It builds, Linton said, “on a unique environment at Vanderbilt for studying HDL function in human disease because of our expertise in HDL metabolism, mediators of oxidative stress and the biology of microRNAs.”