Cuff-induced vascular intima thickening is influenced by titration of the Ace gene in mice.
We tested the hypothesis that small changes in angiotensin I-converting enzyme (ACE) expression can alter the vascular response to injury. Male mice containing one, two, three, and four copies of the Ace gene with no detectable vascular abnormality or changes in blood pressure were submitted to cuff-induced femoral artery injury. Femoral thickening was higher in 3- and 4-copy mice (42.4 +/- 4.3% and 45.7 +/- 6.5%, respectively) compared with 1- and 2-copy mice (8.3 +/- 1.3% and 8.5 +/- 0.9%, respectively). Femoral ACE levels from control and injured vessels were assessed in 1- and 3-copy Ace mice, which represent the extremes of the observed response. ACE vascular activity was higher in 3- vs. 1-copy Ace mice (2.4-fold, P < 0.05) in the control uninjured vessel. Upon injury, ACE activity significantly increased in both groups [2.41-fold and 2.14-fold (P < 0.05) for 1- and 3-copy groups, respectively] but reached higher levels in 3- vs. 1-copy Ace mice (P < 0.05). Pharmacological interventions were then used as a counterproof and to indirectly assess the role of angiotensin II (ANG II) on this response. Interestingly, ACE inhibition (enalapril) and ANG II AT(1) receptor blocker (losartan) reduced intima thickening in 3-copy mice to 1-copy mouse values (P < 0.05) while ANG II treatment significantly increased intima thickening in 1-copy mice to 3-copy mouse levels (P < 0.05). Together, these data indicate that small physiologically relevant changes in ACE, not associated with basal vascular abnormalities or blood pressure levels, do influence the magnitude of cuff-induced neointima thickening in mice.
Lacchini
Silvia
S
Heart Institute (InCor), University of São Paulo Medical School, São Paulo, SP, Brazil.
Heimann
Andrea S
AS
Evangelista
Fabiana S
FS
Cardoso
Leandro
L
Silva
Gustavo J J
GJ
Krieger
José E
JE
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020212:Carotid Artery Injuries / Q000503:physiopathology; D003250:Constriction; D004656:Enalapril / Q000494:pharmacology; D005263:Femoral Artery / Q000187:drug effects / Q000201:enzymology / Q000293:injuries; D018628:Gene Dosage; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013050:Spectrometry, Fluorescence; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A; D019808:Losartan