Nancy J. Brown, MD
C.N.H. Long Professor of Internal Medince.
Jean and David W. Wallace Dean of the Yale School of Medicine
hypertension, renin-angiotensin-aldosterone, kallikrein-kinin, angiotensin-converting enzyme inhibitors, angioedema, fibrinolysis, inflammation, atrial fibrillation
Research in our laboratory focuses on the following areas:
1. Role of the renin-angiotensin-aldosterone system in modulating oxidative stress, inflammation and fibrinolysis.
The renin-angiotensin-aldosterone system (RAAS) is one of the major blood pressure regulating systems in the body. The small peptide angiotensin II, Ang II, raises blood pressure by constricting blood vessels and increasing salt retention, in part by stimulating synthesis of the mineralocorticoid aldosterone. We now understand that the RAAS has other detrimental effects on the blood vessels, heart and kidney. Both Ang II and aldosterone cause inflammation and fibrosis and promote clotting. Studies in our laboratory are examining the mechanisms of these effects.
2. Role of the renin-angiotensin-aldosterone system in regulating glucose homeostasis.
Sixty per cent of Americans are obese and both the activity of the RAAS and inflammation are increased in obesity. Obese individuals are at increased risk for the development of diabetes and hypertension, but drugs that interrupt the RAAS seem to decrease this risk. Studies in our laboratory are helping us to understand the mechanism for this effect so that we may devise better strategies to prevent diabetes.
3. Cardiovascular effects of the kallikrein-kinin system.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the two major classes of drugs currently used to interrupt the renin-angiotensin-aldosterone system. ACE inhibitors decrease the formation of Ang II, whereas ARBs block the effect of Ang II at its major receptor. In addition, ACE inhibitors prevent the breakdown of and promote the actions of bradykinin, a peptide in the body that lowers blood pressure. Bradykinin has other beneficial effects, like increasing tissue-type plasminogen activator from the endothelium. Bradykinin can also have detrimental effects, promoting inflammation. The net beneficial or detrimental effect of bradykinin may depend on the health of the blood vessels.
4. Role of arachidonic acid monooxygenases and epoxygenases in the regulation of blood pressure and cardiovascular risk.
Bradykinin exerts its blood pressure lowering effects, in part, through effects on cytochrome P450 (CYP450) epoxygenases that form eicosatetraenoic acids (EETs) from arachidonic acid. EETs relax blood vessels. EETs formed in the kidney also stimulate salt excretion. Animal studies suggest that, in the kidney, EET formation is regulated in part by 20-hydroxyeicosatetraenoic acid 20-HETE, the product of CYP4A11. Research in our laboratory indicates that a loss-of-function variant of the gene encoding CYP4A11 is associated with high blood pressure and progression of renal disease. We are refining our understanding of how these systems regulate blood pressure in humans and how they interact with the RAAS.
5. Contribution of peptidases to angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.?
Despite the many beneficial effects of ACE inhibitors, this class of medications can cause swelling of the lips, tongue, or face, a side effect called angioedema. Likely, this side effect results from decreased breakdown of bradykinin and another peptide called substance P. We have determined groups of patients who are at increased risk for angioedema. Studies in our laboratory have identified one pathway involved in angioedema and will allow us to better predict risk and prevent the side effect.
6. Pharmacogenetics of the renin-angiotensin-aldosterone and kallikrein-kinin sytems.?
Genetic factors modulate all of the processes described above. One goal of our laboratory is to identify these factors in order to better predict individual responses to drugs such as ACE inhibitors, ARBs, aldosterone receptor blockers and renin inhibitors.