ACE, ACE inhibitors, and other JNK.

The renin-angiotensin system (RAS) plays a pivotal role in the regulation of blood pressure, volume homeostasis, vascular function, and cell growth. In what is considered the classic RAS, renin is released from juxtaglomerular cells of the kidney into the circulation where it converts angiotensinogen from the liver to angiotensin I. Angiotensin I is subsequently hydrolyzed by a peptidyl dipeptidase, angiotensin-converting enzyme (ACE), from the lung to form angiotensin II. Investigators have been cognizant of renin for more than a century after its initial discovery in 1898 by Tigerstedt and Bergman (see review1). However, it was not until the middle of the 20th century that the remaining components of RAS were purified and identified by Skeggs and colleagues. These included angiotensinogen, angiotensin I, angiotensin II, and ACE, which at the time was termed “hypertensin-converting enzyme” (see review1). Since that time, many components of the RAS, especially ACE, have received considerable attention as a focal point for researchers interested in better understanding the regulation of the cardiovascular system. Considering the rapid progress in understanding the molecular physiology of RAS and its many complexities, it should not be surprising that details would continue to emerge. It is unexpected, however, that after 100 years of research major new concepts would surface requiring scientists and clinicians to rethink the system and its role in cardiovascular regulation. Even more astounding is that over the span of 3 years, two major conceptual changes would have to be considered regarding ACE. The first surprise occurred in 2000 with the discovery of ACE2, a “homologue” of ACE capable of producing angiotensin peptides such as Ang-(1-7), which may have vasodilator properties.2,3 Thus, ACE and ACE2 may ultimately have opposing physiological effects. The second new concept is described in this issue of Circulation Research.4