I believe that this paper was the first to demonstrate an antagonism between the nuclear factor PPAR gamma activation and angiotensin II stimulation at the level of the vasculature. These vascular protective properties were independent of the metabolic properties for which these agents were clinically developed. Angiotensin II has for many years been implicated in the pathogenesis of cardiovascular disease. Angiotensin II induces vasoconstriction, vascular growth, and inflammation that play a role in atherosclerosis, as well as the vascular disease associated with hypertension. Our results have generated the hope that we indeed proposed in this and successive papers, that these agents may be useful in the prevention of cardiovascular disease in high-risk patients , including diabetic subjects who are treated with these insulin-sensitizing agents, but also patients with the metabolic syndrome or others who are at risk of developing cardiovascular disease.

I believe indeed that following this and other studies suggesting a role of PPAR gamma and other PPARs (alpha, beta/delta) as "good guys" in relation to vascular disease, this has prompted investigators and the pharmaceutical industry to attempt to capitalize on these favorable cardiovascular properties of the agents that activate PPARs, with the idea of using them in cardiovascular prevention, independent of their metabolic properties.

Our study demonstrated that agents that are known to sensitize the skeletal muscle to insulin, and are therefore clinically used to treat diabetes, also have properties that allow them to block the blood-vessel constricting, blood-pressure raising, and pro-inflammatory actions that damage blood vessels, of the substance called angiotensin II; which has been clearly implicated in the mechanisms leading to diseases of the cardiovascular system and the kidney, such as high blood pressure, heart attacks, heart failure, stroke, and kidney failure. This suggests that these agents or other similar drugs may be useful for the prevention and treatment of some of these conditions.

Our area of interest is hypertension. Diabetes puts hypertensive patients at the highest vascular risk. After hearing a lecture on PPARs at the American Heart Association Scientific Sessions, I decided to start working on these agents that seemed to me intuitively to have potential for favorable vascular effects. We did some studies on the presence of PPARs in the vascular smooth muscle of rats, then in genetically hypertensive rats, and then decided that it would be important to see whether PPARs acted as endogenous antagonists of angiotensin II, which plays an important role in hypertension. Since then, we have shown PPAR gamma (and alpha) activation to be effective against other vascular pathogenic agents in other models of hypertension (published in Hypertension 2002; ATVB 2003).