Inhibition of PAI-1 as a Potential Treatment for Atherosclerosis

Researchers are investigating a drug candidate that inhibits plasminogen activator inhibitor-1 (PAI-1) as a potential treatment to slow the progression of atherosclerosis, in which fatty deposits build up in blood vessel walls. This leads to narrowing, structural failure of blood vessels, or blockage when the deposits grow unstable and rupture. The publicity materials in this case fail to join some of the dots to explain why this is interesting in the broader context; the evidence points to influence on cellular senescence as a possible mechanism for the effect here. Past research has shown that PAI-1 is involved in steering cells to a senescent state, and in the activities of cells while senescent. Further, senescent cells drive a sizable fraction of the growth and instability in the fatty plaques of atherosclerosis, and removing them slows the development of the condition. So we might take this sort of drug development research as further support for the benefits to be realized from bringing clearance of senescent cells to the clinic.

Approximately 2,200 Americans die each day from heart attacks, strokes and other cardiovascular diseases. The most common cause is blocked blood vessels that can no longer supply oxygen and nutrients to the heart and brain. A recent study has shown that a protein inhibitor drug prevents these blockages, and could be a new therapeutic approach to prevent heart attack, stroke and other diseases caused by blocked blood vessels. "Arteries are living hoses that narrow and enlarge in order to regulate blood flow to organs and muscles. Smooth muscle cells in the artery regulate blood flow by constricting and relaxing. However, when chronic inflammation occurs in a blood vessel - typically in response to diabetes, high cholesterol and cigarette smoking - the smooth muscle cells in the walls of arteries change their behavior. They gradually accumulate inside the artery and narrow the blood vessel. In the case of coronary arteries, which supply blood to heart muscle cells, this process produces blockages that can lead to a heart attack."

Plasminogen activator inhibitor-1, or PAI-1, is a naturally occurring protein within blood vessels that controls cell migration. With diseases such as diabetes and obesity, PAI-1 over-accumulates in blood vessels. This promotes blockage formation. This process occurs not only in arteries, but also in vein grafts in patients who have undergone coronary artery bypass graft surgery. The research team studied PAI-039, also known as tiplaxtinin, an investigational drug not yet used to treat humans. The researchers found that PAI-039 inhibited the migration of cultured human coronary artery smooth muscle cells, and prevented the development of blockages in arteries and bypass grafts in mice. "We found that PAI-039 decreased blockage formation by about 50 percent, which is a powerful effect in the models we used. In addition to reducing vascular blockages, inhibiting PAI-1 also produces a blood thinning effect that prevents the blood clots that trigger most heart attacks and strokes." If future studies are successful, PAI-039 or similar drugs could be used to prevent blockages in arteries and bypass grafts.



In slightly related news CNBC ran an article today about the future direction of heart disease research. There was this quote I found very positive:

"The future of cardiovascular research is to stop the disease before it starts. It sounds simple, but we haven't really done that." -Dr. Steven Houser, president of the American Heart Association

Posted by: Corbin at December 22nd, 2016 11:02 AM

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