Angiotensin-converting enzyme inhibition attenuates hypofibrinolysis and reduces cardiac perivascular fibrosis in genetically obese diabetic mice.
BACKGROUND
Obesity and insulin resistance are associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathic phenomena, and increased concentrations and activity in blood of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of fibrinolysis.


RESULTS
To determine whether hypofibrinolysis in blood and tissues and its potential sequelae could be attenuated pharmacologically, we studied genetically modified obese mice. By 10 weeks of age, obese mice exhibited increases in left ventricular weight and glucose and immunoreactive insulin in blood. PAI-1 activity in blood measured spectrophotometrically was significantly elevated as well. The difference compared with values in lean controls widened by 20 weeks of age. Perivascular fibrosis in coronary arterioles and small coronary arteries was evident in obese mice 10 and 20 weeks of age, paralleling increases in PAI-1 and tissue factor expression evident by immunohistochemical image analysis, in situ hybridization, and reverse transcription-polymerase chain reaction. Inhibition of ACE activity initiated in obese mice 10 weeks of age and continued for 20 weeks arrested the increase in PAI-1 activity in blood and in cardiac PAI-1 and tissue factor mRNA as well as coronary perivascular fibrosis.


CONCLUSIONS
Thus, inhibition of proteo(fibrino)lysis and augmented tissue factor expression in the heart precede and may contribute to the coronary perivascular fibrosis seen with obesity and insulin resistance. Furthermore, inhibition of ACE activity can attenuate all 3 phenomena.
Zaman
A K
AK
Department of Cardiovascular Medicine, CREST, Hokkaido University School of Medicine, Sapporo, Japan.
Fujii
S
S
Sawa
H
H
Goto
D
D
Ishimori
N
N
Watano
K
K
Kaneko
T
T
Furumoto
T
T
Sugawara
T
T
Sakuma
I
I
Kitabatake
A
A
Sobel
B E
BE
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003331:Coronary Vessels / Q000737:chemistry / Q000473:pathology*; D003920:Diabetes Mellitus / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D005342:Fibrinolysis / Q000187:drug effects*; D005355:Fibrosis / Q000517:prevention & control; D006352:Heart Ventricles / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009206:Myocardium / Q000473:pathology; D009765:Obesity; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects*; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D013841:Thiazepines; C055603:temocapril hydrochloride; D013925:Thromboplastin; D007703:Peptidyl-Dipeptidase A