A story of two ACEs.
According to the World Health Organization predictions cardiovascular diseases will be the leading cause of death by the year 2020. High blood pressure is a major risk factor for myocardial infarction, cerebrovascular disease, and stroke. Modulation of the renin-angiotensin system, particularly inhibition of the angiotensin-converting enzyme (ACE), has become a prime strategy in the treatment of hypertension and heart failure. Recently the gene of a new ACE, termed ACE2, has been characterized. The ACE2 gene maps to defined quantitative trait loci on the X chromosome in three different rat models of hypertension, suggesting ACE2 as a candidate gene for hypertension. In mice the targeted disruption of ACE2 resulted in increased systemic angiotensin II levels, impaired cardiac contractility, and upregulation of hypoxia-induced genes in the heart. Since mice deficient in both ACE2 and ACE show completely normal heart function, it appears that ACE and ACE2 negatively regulate each other. The mechanisms and physiological significance of the interplay between ACE and ACE2 are not yet elucidated, but it may involve several new peptides and peptide systems. In view of drug development the increasing complexity of the renin-angiotensin system offers both challenge and opportunity to develop new and refined treatment strategies against cardiovascular diseases.
Danilczyk
Ursula
U
Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, M5G 2C1, Toronto, Ontario, Canada.
Eriksson
Urs
U
Crackower
Michael A
MA
Penninger
Josef M
JM
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure; D002268:Carboxypeptidases / Q000235:genetics* / Q000502:physiology; D002318:Cardiovascular Diseases / Q000235:genetics / Q000628:therapy; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009200:Myocardial Contraction; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000502:physiology*; D017434:Protein Structure, Tertiary; D051381:Rats; D012084:Renin-Angiotensin System; D013379:Substrate Specificity; D015854:Up-Regulation
D018076:DNA, Complementary; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2