Angiotensin-Converting Enzyme Inhibition Attenuates Hypofibrinolysis and Reduces Cardiac Perivascular Fibrosis in Genetically Obese Diabetic Mice
Open accessAbstract
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. Methods and 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.
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In ob/ob mice, fibrosis occurs mainly in the coronary perivascular region.
“In ob/ob mice, fibrosis occurs mainly in the coronary perivascular region (391, 392).”
From Cardiac remodeling in obesity (2008) · cites this paper as [392]
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Renin-Angiotensin-Aldosterone System in Diabetic Cardiovascular Complications
Balakrishnan, V. S. (2023) · Contemporary cardiology · doi:10.1007/978-3-031-13177-6_31 · Cited by 2 · see citing works
Hammad, A. S. A., Ahmed, A. F., Heeba, G. H., & Taye, A. (2018) · Journal of advanced Biomedical and Pharmaceutical Sciences · doi:10.21608/jabps.2018.5175.1022 · Cited by 2 · see citing works
Lopes-Virella, M. F., & Virella, G. (2023) · Contemporary cardiology · doi:10.1007/978-3-031-13177-6_9 · Cited by 2 · see citing works
The Renin—Angiotensin System in Diabetic Cardiovascular Complications
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Sobel, B. E. (2015) · Cardiovascular medicine · doi:10.1007/978-1-4471-2828-1_6 · Cited by 1 · see citing works
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Anti-thrombotic therapy for metabolic syndrome
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Tallquist, M. D. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.99828-3
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Obesity-Associated Cardiac Fibrosis: Mechanisms and Emerging Therapeutic Targets
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- Authors
- Zaman, A. K. M. T., Fujii, S., Sawa, H., Goto, D., Ishimori, N., Watano, K., Kaneko, T., Furumoto, T., Sugawara, T., Sakuma, I., Kitabatake, A., & Sobel, B. E.
- Affiliations
- University of Vermont (US)
- Venue
- Circulation
- Published
- 2001-06-26
- Volume
- 103
- Issue
- 25
- Pages
- 3123-3128
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W1965182744
- Cited by
- 68
- References
- 39
- Citations by year
- 2026: 1 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 1 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 3 · 2014: 3 · 2013: 1 · 2012: 1
- FWCI
- 4.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Circulation (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- angiotensin-converting enzyme inhibition, hypofibrinolysis, plasminogen activator inhibitor-1, tissue factor, obesity, insulin resistance, coronary arterioles, diabetic mice, left ventricular hypertrophy, coronary disease
- MeSH terms
- Angiotensin-Converting Enzyme Inhibitors, Animals, Blood Glucose, Body Weight, Coronary Vessels, Diabetes Mellitus, Fibrinolysis, Fibrosis, Heart Ventricles, Immunohistochemistry, Peptidyl-Dipeptidase A, Male, Mice, Inbred C57BL, Mice, Obese, Myocardium, Obesity, Organ Size, RNA, Messenger, Thiazepines, Thromboplastin, Plasminogen Activator Inhibitor 1, In Situ Hybridization, Mice
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