A genetic variant of ACE increases cell survival: a new paradigm for biology and disease.
The human angiotensin converting enzyme (ACE) polymorphism is caused by an Alu element insertion resulting in three genotypes (Alu+/+, Alu+/-, Alu-/-, or ACE-II, ACE-ID, and ACE-DD, respectively), with ACE-II displaying lower ACE activity. The polymorphism is associated with athletic performance, aging, and disease. Population studies, however, were confounding because variants of the polymorphism appeared to fortuitously correlate with health and various pathological states. To clarify the functional role of the polymorphism, we studied its direct effect on cell survival. ACE-II (Alu+/+) human endothelial cells (EC) had lower angiotensin-II levels and 20-fold increased viability after slow starvation as compared to ACE-DD cells (Alu-/-). By RT-PCR, only ACE-II cells expressed the pluripotent/stem cell-maintenance factors nanog, numb, and klotho. ACE inhibition by captopril in ACE-DD cells mimicked the ACE-II genotype. These results provide the first evidence of a functional role for a naturally occurring polymorphism, having broad implications for human biology, longevity, and disease.
Hamdi
Hamdi K
HK
Department of Ophthalmology, University of California, Irvine, 101 The City Drive Bldg. 55, Room 202, Orange, CA 92868, USA. hhamdi@uci.edu
Castellon
Raquel
R
D020087:Alu Elements / Q000235:genetics; D000803:Angiotensin I / Q000096:biosynthesis; D000804:Angiotensin II / Q000096:biosynthesis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D001483:Base Sequence; D002216:Captopril / Q000494:pharmacology; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007527:Isoenzymes; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA
D000806:Angiotensin-Converting Enzyme Inhibitors; D007527:Isoenzymes; D000804:Angiotensin II; D000803:Angiotensin I; D002216:Captopril; D007703:Peptidyl-Dipeptidase A