Signaling hypertrophy: how many switches, how many wires.

Abstract

Despite the longstanding appreciation by cardiologists of its fundamental importance, the hypertrophic process nevertheless remains an enigma. Key questions have not been answered. What are the outside-in signals that initiate this process? How many pathways can communicate these signals? Do they all converge to trigger the same orchestrated inside-out cardiac response? Cardiac hypertrophy appears to encompass more than one phenotype, even at the cellular level. Is there a good form of hypertrophy (a beneficial myocyte response) versus bad hypertrophy (the dysfunctional response)? But with the heart, the situation is, of course, even more complicated. The architecture of this organ is an important determinant of function; hence, alteration of the normal geometry of the heart as a consequence of hypertrophy can have important consequences—again, some worse than others. The myocardium, particularly in the setting of severe hypertrophy, can pay a high price in terms of its requirements for both substrates and O2. Thus, it is no surprise that cardiologists are always eagerly awaiting the chance to turn the next page on this story, hoping to find the answers to the above questions. Over the past 50 years at least, cardiologists, physiologists, biochemists, pharmacologists, and now molecular biologists have worked to understand this process, with each discipline finding, of course, what it is best prepared to recognize. The molecular signals underlying the genesis of hypertrophy would be a wonderful prize to garner. How many switches are there? Do they connect to multiple sets of wires, and where do these wires terminate? In a study reported in this issue of Circulation ,1 one of the sharper tools of modern-day biology is used to sever the connections to one of these switches, the angiotensin II type IA receptor, which is the dominant angiotensin II type I receptor subtype in the murine …