Angiotensin-converting enzyme gene mutations, blood pressures, and cardiovascular homeostasis

Abstract

A common polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE in humans, Ace in mice) is associated with differences in circulating ACE levels that may confer a differential risk for cardiovascular diseases. To study the effects of genetically determined changes in Ace gene function within a defined genetic and environmental background, we have studied mice having one, two, or three functional copies of the Ace gene at its normal chromosomal location. ACE activities in the serum increased progressively from 62% of normal in the one-copy animals to 144% of normal in the three-copy animals (P < 10(-15), n = 132). The blood pressures of the mice having from one to three copies of the Ace gene did not differ significantly, but the heart rates, heart weights, and renal tubulointerstitial volumes decreased significantly with increasing Ace gene copy number. The level of kidney renin mRNA in the one-copy mice was increased to 129 +/- 9% relative to that of the normal two-copy mice (100 +/- 4%, P = .01, n = 16). We conclude that significant homeostatic adaptations successfully normalize the blood pressures of mice that have quantitative changes in Ace gene function. Our results suggest only that quantitative changes in expression of the Ace gene will observably affect blood pressures when accompanied by additional environmental or genetic factors that together with Ace exceed the capacity of the homeostatic mechanisms.