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Regulation of vascular smooth-muscle cell growth by angiotensin II
1Division of Cardiovascular Medicine, Stanford University School of Medicine, California, USA.
Insights
Angiotensin-converting enzyme (ACE) plays a key role in cardiovascular diseases by promoting abnormal vascular cell growth. Inhibiting local ACE in tissues is more effective than blocking circulating ACE in preventing lesion development.
Area of Science:
- Cardiovascular Biology
- Vascular Cell Biology
- Pharmacology
Background:
- Abnormal vascular smooth muscle cell growth is central to cardiovascular diseases like hypertension, atherosclerosis, and restenosis.
- Angiotensin, potentially produced locally by tissue-converting enzyme, is implicated in regulating vascular structure and cell growth.
Purpose of the Study:
- To investigate the role of angiotensin-converting enzyme (ACE) in cardiovascular disease development, particularly atherosclerosis.
- To determine if local tissue ACE activity or circulating ACE activity is more critical in disease processes.
Main Methods:
- Animal models were used to study ACE expression in injured vessels and the efficacy of ACE inhibitors on neointimal lesion development.
- Immunohistochemistry was employed to detect ACE in human coronary atherosclerotic plaques.
- Cell culture experiments examined ACE expression in macrophages derived from monocytes, including the effects of acetylated low-density lipoproteins.
Main Results:
- In animal models, injured vessels showed high ACE expression, and ACE inhibitor efficacy correlated better with inhibition of tissue ACE than circulating ACE.
- ACE was found within human atherosclerotic plaques, co-localizing with macrophage clusters.
- Differentiated macrophages and those treated with acetylated LDL exhibited increased ACE expression.
Conclusions:
- Local tissue ACE activity appears to be a significant factor in cardiovascular disease progression, including neointimal lesion development.
- ACE is present in human atherosclerotic lesions and may be upregulated in macrophages, suggesting a role in atherosclerosis.
- Further research is needed to fully elucidate the role of ACE in human atherosclerosis.
Abstract:
Abnormal growth of vascular smooth-muscle cells is a characteristic of many cardiovascular diseases. This abnormal growth occurs during hypertension-induced vascular hypertrophy, during the development of an atherosclerotic lesion, and during the development of a restenotic lesion following angioplasty. It is becoming increasingly apparent that among the many factors that may influence vascular structure, angiotensin may play a major role. Angiotensin-converting enzyme (ACE) inhibitors decrease hypertension-induced vascular hypertrophy, and, in many animal models, these inhibitors block the development of atherosclerosis and the development of an injury-induced neointimal lesion. Evidence suggests that the local production of angiotensin via tissue-converting enzyme may play an important role in these growth effects. We have demonstrated in animal models that injured vessels express high levels of ACE. Moreover, we have shown that the ability of an ACE inhibitor to block neointimal development correlates better with its ability to inhibit tissue ACE than with its ability to block circulating ACE. The role of angiotensin in human atherosclerosis is not clear. In an immunohistochemical study of human coronary arteries, we have obtained evidence that ACE is present within the atherosclerotic plaque, associated with regions of macrophage clustering. Moreover, in cell culture, monocytes induced to differentiate into macrophages express high levels of ACE. Treatment of these cells with acetylated low density lipoproteins results in a further increase in ACE expression. These results support the hypothesis that ACE may play a role in the development of atherosclerosis. Further studies, however, are required to precisely define this role.