Drugs known as thiazolidinediones (TZDs), which are used to treat type 2 diabetes, seem to come with an added side benefit: They lower blood pressure. Now, researchers reporting in the March issue of Cell Metabolism, a publication of Cell Press, provide new evidence as to why.
The researchers show that so-called peroxisome proliferator-activated receptor Ó (PPARÓ)—a molecule that stands at the crossroads of metabolic and cardiovascular diseases and is the target of TZDs—plays an unanticipated protective role in the blood vessel wall.
“The incidence of obesity and diabetes and their cardiovascular consequences has reached epidemic proportions, justifying the enormous effort to identify pathways and molecules involved in their pathogenesis,” said Curt Sigmund of the University of Iowa. “This study provides evidence for a pivotal role of smooth muscle PPARÓ in the regulation of vascular structure and function and provides a molecular explanation for some of the beneficial cardiovascular effects of TZD drugs.”
The importance of PPARÓ was made clear when scientists found it to be the target of insulin-sensitizing TZDs, the researchers noted. Several studies also indicated that people taking TZDs for diabetes tended toward lower blood pressure and signs of other cardiovascular improvements. But that view was recently challenged by a still controversial study suggesting that the risk of adverse cardiovascular events, including heart attack and death, may actually rise in patients taking the TZD rosiglitazone (Avandia), added Sigmund’s group. “Accordingly,” they wrote, “there is an urgent need not only to assess the beneficial and consequential effects of TZDs but also to understand the fundamental mechanisms controlling the metabolic and cardiovascular function of PPARÓ itself.”
To test PPARÓ’s blood vessel role, the researchers developed mice lacking the gene encoding PPARÓ in smooth vascular muscle. These animals showed changes in their blood vessels, characterized by a failure to vasodilate, or expand, in response to nitric oxide. The animals also developed high blood pressure and other “striking alterations” in the structure and function of their vasculature. “If this protein is deactivated, it appears that the protective pathways can’t be activated,” Sigmund said.
As for studies suggesting detrimental effects of TZDs, Sigmund said, like most things, balance in this protein is probably key. “There will be interest in developing variations of these molecules that keep all the ‘goodies’ and get rid of the bad,” he said.
The researchers include Carmen M. Halabi, Andreas M. Beyer, Willem J. de Lange, Henry L. Keen, Gary L. Baumbach, Frank M. Faraci, and Curt D. Sigmund, all of the Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.