Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasoconstricting peptide angiotensin II and inactivates the vasodilating peptide bradykinin. The gene encoding ACE is composed of two homologous regions and codes for both a somatic and testis isoenzyme. Experiments with hypertensive rats and some, but not other, studies of humans suggest that sequences at or linked to the gene influence blood pressure. The testis-specific form of ACE has its own promoter within intron 12 (ref. 14), is encoded by the 3' region of the gene, and is found only in postmeiotic spermatogenic cells and sperm. Its function is unknown. Here we investigate the role of the Ace gene in blood pressure control and reproduction using mice generated to carry an insertional mutation that is designed to inactivate both forms of ACE. All homozygous female mutants were found to be fertile, but the fertility of homozygous male mutants was greatly reduced. Heterozygous males but not females had blood pressures that were 15-20 mm Hg less than normal, although both male and female heterozygotes had reduced serum ACE activity.

Common variants of the angiotensin-converting enzyme (ACE) gene ( ACE in humans, Ace in mice) associated with changes in circulating ACE activities have been suggested to confer differential risks for atherosclerosis. Using a mouse model of atherosclerosis induced by heterozygosity for apolipoprotein E gene disruption and an atherogenic diet, we have studied the impact on atherogenesis of a mutation that changes the level of function of Ace . We find that this genetically determined change does not influence the size or complexity of atherosclerotic lesions. Ace genotype was not a significant determinant of lesion size in female (+/+=12.9±1.5 and +/-=1 1.7±1.6 μm 2 ×l0 4 ) or male (+/+=0.95±0.25 and +/-=1.83±0.59 μm 2 ×l0 4 ) mice; however, lesions were significantly larger ( P <.001) in female than male mice. Ace genotype also did not affect lesion complexity; however, lesions in females showed significantly increased frequency of cholesterol clefts, acellular cores, fibrous caps, and calcifications compared with those in males. The hypothesis that genetic variation in the level of ACE gene expression affects the development of atherosclerosis is not supported by these findings. ( Arterioscler Thromb Vase Biol. 1997;17:1245-1250.)