|Stanford's Cornelia Weyand|
A team at Stanford University School of Medicine has pinpointed a class of immune cells that may be the key drivers of coronary artery disease (CAD). The findings from this study may present a new strategy to target CAD--a disease that causes over a half of all deaths in the US.
The study was conducted by senior author Cornelia Weyand and lead author Tsuyoshi Shirai. They published their findings in The Journal of Experimental Medicine last month.
The Stanford team uncovered a defect in glucose metabolism by a group of immune cells found in the atherosclerotic plaques of arteries. Plaques are fatty deposits laid down in vessel walls throughout our lives and as they get larger they become vulnerable to rupture, causing life threatening conditions. The team believes this abnormal metabolism is driving immune cells into a hyper-inflammatory state, worsening the situation.
They proved this by blocking the glucose overconsumption, as well as other associated biochemical events in the cell's metabolism, and found they could reverse the hyperinflammatory state.
This work supports other groups that argue more attention needs to be placed on the state of chronic inflammation in the artery--rather than solely the amount of fatty deposits in the artery.
CAD is known as the "silent killer" due to its slow and progressive buildup of plaque in our arteries from a young age. It puzzled the researchers therefore why such a gradual process could suddenly cause heart attacks or strokes.
"It's been unclear where the inflammation comes from," Weyand said. Digging deeper into the composition of plaques, it is now known that there are a type of immune cell called macrophages that have a beneficial and detrimental role in CAD. The beneficial role comes from the M2 macrophages that help to clean up a damaged cell and encourage new cell growth, while the detrimental role comes from M1 macrophages that behave in a highly inflammatory way.
"Some believe that coronary artery disease patients' macrophages are so preoccupied with their inflammatory power trip they neglect their clean-up tasks," Weyand said.
The group isolated monocytes (the precursors of macrophages) from the blood of a large cohort of patients with and without CAD. They then cultured these and experimentally forced them to become macrophages. When they did this they noted monocytes from CAD patients were predisposed to become M1 macrophages that produced a well-known inflammatory protein called interleukin-6, or IL-6.
"Even before taking up residence in arterial plaque and becoming full-fledged macrophages, these patients' monocytes were already leaning toward becoming inflammatory," Weyand said. "If you simply overfeed normal monocytes or macrophages, they don't turn in into high IL-6 producers. We wondered why."
They observed two things, firstly the mitochondria of the macrophages derived from CAD patients were churning out many more free radicals, and secondly, this surge in free radicals was being caused by the excessive uptake of glucose. Free radicals contribute to oxidative stress and can provide an inflammatory trigger in vulnerable cells.
"The primary problem, we learned, is that these macrophages take up glucose at a higher rate than normal cells do," said Weyand. "That causes them to break it down faster, overheating their mitochondria, which then produce too many free radicals."
They concluded the study by finding that an enzyme was being changed by the excessive free radicals in CAD derived macrophages. The enzyme, called PKM2, usually helps to breakdown glucose into energy but since there was already bountiful glucose uptake it instead headed for the nucleus activating IL-6 by an intermediate transcription factor, STAT3.
Weyand and her team believe that hitting PKM2 with a drug preventing its translocation to the nucleus may be a new therapeutic angle for lowering inflammation in the macrophages of patients with CAD.
- here's the release