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Calcium channel blockers enhance cholesteryl ester hydrolysis and decrease total cholesterol accumulation in human
1Department of Medicine Hematology-Oncology, Cornell University Medical College, New York, NY 10021.
Insights
Calcium channel blockers (CCBs) increase cholesteryl ester (CE) hydrolysis in human arteries, reducing CE accumulation. This suggests CCBs may act as anti-atherosclerotic agents by mobilizing arterial wall CE.
Area of Science:
- Cardiovascular Pharmacology
- Atherosclerosis Research
- Cellular Metabolism
Background:
- Calcium channel blockers (CCBs) treat angina and hypertension by inhibiting calcium influx.
- CCBs are known to prevent cholesteryl ester (CE) accumulation in animal models of atherosclerosis.
- The cellular mechanisms underlying CCB-mediated prevention of CE accumulation in humans are undefined.
Purpose of the Study:
- To investigate whether CCBs enhance CE hydrolysis and reduce CE accumulation in human arterial cells.
- To elucidate the cellular mechanisms involved in CCB action on arterial CE metabolism.
Main Methods:
- Analysis of cholesteryl ester (CE) metabolic cycle activities in human aortic tissues from patients undergoing coronary artery bypass surgery.
- Comparison of CE hydrolysis and synthesis between patients treated with CCBs (nifedipine or diltiazem) and untreated patients.
- Measurement of intracellular cyclic AMP levels in aortic tissues.
Main Results:
- Patients treated with CCBs showed a threefold increase in arterial CE hydrolytic activities compared to untreated patients.
- CE synthetic activity remained unaffected by CCB treatment.
- Cyclic AMP levels were significantly elevated (twofold to threefold) in CCB-treated patients' aortic tissue.
- Both free and esterified cholesterol levels were significantly reduced in aortic tissue from patients taking CCBs.
Conclusions:
- CCBs increase CE hydrolysis in human aortic tissue, mediated by increased intracellular cyclic AMP.
- This increased hydrolysis leads to a reduction in CE accumulation.
- These findings support the hypothesis that CCBs possess anti-atherosclerotic properties by mobilizing stored CE in the arterial wall.
Abstract:
Calcium channel blockers (CCBs), which are used clinically for treatment of angina and hypertension, are known to inhibit calcium influx into arterial smooth muscle cells and thereby decrease smooth muscle cell contraction. In addition, they prevent cholesteryl ester (CE) accumulation, the hallmark of human atherosclerosis, in arteries of cholesterol-fed animals by cellular mechanisms that remain undefined. To assess whether CCBs enhance CE hydrolysis and reduce CE accumulation in human arterial cells, we measured activities of the CE metabolic cycle in aortic tissues that were stripped of endothelial cells and adventitia from 35 patients undergoing coronary artery bypass surgery. Patients who were treated with either nifedipine or diltiazem (n = 23) for several months demonstrated a threefold increase in arterial CE hydrolytic activities compared with untreated patients. This difference was independent of serum cholesterol levels, age, or treatment with other medications. No effects were observed on CE synthetic activity. Cyclic AMP levels in the aortic tissue of patients treated with CCBs were also significantly elevated twofold to threefold. In addition, both free and esterified cholesterol were significantly reduced in aortic tissue from patients taking CCBs compared with untreated patients. These data are the first to show that CCBs can increase CE hydrolysis in human aortic tissue by increasing intracellular cyclic AMP with resultant decrease in CE accumulation. Collectively, these findings support the hypothesis that CCBs can act as antiatherosclerotic agents in human tissue by mobilizing stored CE in the arterial wall.