ACE gene dosage modulates pressure-induced cardiac hypertrophy in mice and men.

The influence of genetic factors on complex phenotypes is context dependent, posing a challenge to quantify the role of single gene variants on this process. Moreover, redundancy and reserve capacity among control systems prevent most physiological stimuli to destabilize these processes. To test whether small gene perturbation can disrupt this equilibrium under pathological conditions, mice harboring one, two, or three copies of the angiotensin converting enzyme (Ace) gene were submitted to 3 and 6 wk of pressure overload (PO). Direct systolic blood pressure (SBP), as an index of cardiac afterload, and left ventricle mass index (LVMI) were measured. LVMI under normotension was the same regardless of the Ace genotype, but the slopes of the LVMI/SBP curves increased in the three- vs. one-copy group by approximately 50% upon 3- or 6-wk PO. Angiotensin II AT1 receptor blocker treatment produced a significant pressure independent decrease in the LVMI/SBP ratio. Unlike the one-copy group, PO resulted in a significant reduction in angiotensinogen and an increase in Ace mRNA expression accompanied by an increase in cardiac angiotensin II levels in the three-copy group. Similarly, the human ACE D gene variant influenced cardiac mass, estimated by Sokolov-Lyon index, in a sample of 1,507 individuals from an urban population only in individuals in the 4th quartile of the blood pressure distribution. Collectively, these data provide direct evidence that ACE gene dosage per se does not influence cardiac mass but upon a pathological stimulus, such as elevation in blood pressure, it modulates cardiac mass in both mice and humans.