Key Enzyme Is Secreted By Heart Mast Cells -- Weill Cornell Discovery Opens Door To New Cardiovascular Therapies

Renin breaks down a precursor, angiotensinogen, to form angiotensin. Because angiotensin is a major culprit in the development of cardiovascular diseases, the discovery that renin is produced outside the kidneys could revolutionize our therapeutic approach to these conditions.

Researchers Dr. Roberto Levi, Professor of Pharmacology at Weill Cornell Medical College in New York City, and Dr. Randi Silver, Associate Professor of Physiology and Biophysics, believe that their findings apply to all mast cells, not only those found in the heart. Accordingly, mast-cell-derived renin and local angiotensin formation may be implicated in diseases previously not associated with angiotensin.

The discovery was first reported last year in Proceedings of the National Academy of Sciences, but the research is ongoing.

Renin secretion is the initial step in the renin-angiotensin system, which helps regulate blood pressure. Until now, most experts had assumed that only the kidneys could produce renin.

The finding by the Weill Cornell team challenges this traditional paradigm. Indeed, numerous disease states are associated with an increase in the number of mast cells, and Drs. Levi and Silver believe these cells may constitute a significant source of renin outside of the kidneys, at the organ level.

Because renin is the rate-limiting factor in angiotensin production, its availability at the tissue level from mast cells appears to be the source of local angiotensin II production.

Angiotensin II is a potent vasoconstrictor -- a compound that triggers a narrowing of arteries and a concurrent spike in blood pressure -- and is also involved in chronic heart failure. Millions of Americans take ACE inhibitors and angiotensin receptor blockers to fight the effects of angiotensin II.

"Angiotensin can also affect nerve function within the heart, so drugs that target locally produced renin/angiotensin might help treat cardiac nervous system aberrations, such as irregular heartbeat (arrhythmias), particularly in heart attack," Dr. Levi stated.

Drs. Levi and Silver claim that decreasing renin synthesis and release from mast cells may be more advantageous than inhibiting angiotensin II formation and its effects.

"We feel that stopping renin at the onset would be most efficacious in combating the untoward effects of angiotensin II," they said.

"Mast cells are proving to be a unique source of renin that nobody ever thought to look at before," Dr. Silver said. "It's opened up a completely new field."

Mast cells are normally present in small numbers in all organs, and are best known for their role in allergy, shock, wound healing, and defense against pathogens. Increased numbers of mast cells are found in many pathological conditions, including cardiomyopathy and congestive heart failure.

Drs. Levi and Silver's research is funded by an ongoing grant from the National Heart, Lung, and Blood Institute.

Co-researchers on the study include Alicia C. Reid, Christina J. Mackins, Trevor Askwith, Ulrich Schaefer, and Doris Herzlinger -- all of Weill Cornell Medical College.