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PAI-1 affects vascular integrity

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American Diabetes Association 69th Scientific Sessions

Obesity leads to increases in PAI-1, a predictor of MI, stroke and diabetes, according Douglas E. Vaughan, MD, who spoke at a symposium this weekend focused on adipose tissue and atherosclerosis.

“PAI-1 is a key driver of the consequences of obesity … and is an excellent target for inhibition in the obese population,” Vaughan, a member of the Vascular Medicine/Intervention section of the Cardiology Today editorial board, said. “PAI-1 is really about vascular integrity.”

In his overview of the growing obesity and diabetes epidemic and its link with atherosclerosis, Vaughan said that there is “a lot more PAI-1 walking around now than there was 20 years ago.” BMI is the most important predictor of PAI-1 (plasminogen activator inhibitor-1) levels, and it tracks with the components of the metabolic system, he said.

Diabetes and PAI-1

Several prothrombotic effects of obesity are known: impairment of endothelial function, with decreases in nitric oxide; procoagulant augmentation; and platelet activation. Increases in PAI-1 levels are associated with the impairment of fibrinolysis, leading to development of atherosclerosis. Research by Vaughan and others has shown that transgenic mice that overexpressed PAI-1 developed fibrin-rich clots in their coronary arteries that resulted in MI.

“There is an unbelievable amount of PAI-1 in the arterial walls of people with diabetes,” said Vaughan, a professor in the division of cardiology and chairman of the department of medicine at Northwestern University Feinberg School of Medicine.

Statins have only a modest effect on PAI-1 levels, but metformin, TZDs (thiazolidinediones) and ACE inhibitors can lower PAI-1, he said.

Levels of t-PA (tissue plasminogen activator) are also disturbed in obese people, Vaughan said. A failure to release t-PA is a predictor of cardiovascular events in that t-PA inhibits clot formation. “Just being obese inhibits the release of arterial t-PA,” he said.– by Kathy Holliman

For more information:

• Vaughan DE. Role of the pro-coagulant state accompanying obesity. Presented at: American Diabetes Association’s 69th Scientific Sessions; June 5-9, 2009; New Orleans.