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Dihydropyridine calcium antagonist modulates cholesterol metabolism and eicosanoid biosynthesis in vascular cells
A C Nicholson1, O R Etingin, K B Pomerantz
1Department of Biochemistry, Cornell University Medical College, New York, New York.
Abstract:
Recent clinical studies have shown that calcium channel blockers can retard and possibly reduce the angiographic progression of coronary artery disease. Calcium channel blockers also inhibit dietary-induced atherosclerosis in animal models of this disease. In this study, we delineate potential cellular and molecular mechanisms by which nicardipine, a dihydropyridine calcium antagonist, may alter lipoprotein and cholesterol trafficking, affect the regulatory signal transduction pathways involved in accelerating cholesteryl ester (CE) catabolism in vascular smooth muscle cells, and modulate cell-cell interactions of vascular and inflammatory cells. We demonstrate in arterial smooth muscle cells that nicardipine increases 1) LDL binding, uptake, and degradation, 2) RNA transcript levels for the LDL receptor, 3) CE catabolic activity, 4) PGI2 release, and 5) RNA transcript levels for cyclooxygenase. Furthermore, nicardipine blocked cytokine-induced monocyte adhesion to endothelial cells and smooth muscle cells. Taken together, these findings support the hypothesis that nicardipine may function as an anti-atherosclerotic agent by promoting CE catabolism and cholesterol clearance and by reducing monocyte adhesion to the activated endothelium.
Insights
Nicardipine, a calcium channel blocker, may reduce atherosclerosis by enhancing cholesterol breakdown and clearance in artery cells. It also reduces inflammatory cell adhesion, supporting its potential as an anti-atherosclerotic treatment.
Area of Science:
- Cardiovascular Pharmacology
- Molecular Biology
- Atherosclerosis Research
Background:
- Clinical studies suggest calcium channel blockers (CCBs) slow coronary artery disease progression.
- CCBs have demonstrated inhibition of atherosclerosis in animal models.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms of nicardipine's anti-atherosclerotic effects.
- To examine nicardipine's impact on lipoprotein/cholesterol metabolism and vascular cell interactions.
Main Methods:
- Assessed nicardipine's effects on LDL receptor activity, cholesteryl ester (CE) catabolism, and PGI2/cyclooxygenase expression in arterial smooth muscle cells.
- Evaluated nicardipine's ability to inhibit monocyte adhesion to endothelial and smooth muscle cells.
Main Results:
- Nicardipine increased LDL binding, uptake, degradation, and LDL receptor expression.
- Nicardipine enhanced CE catabolic activity and PGI2/cyclooxygenase expression.
- Nicardipine inhibited cytokine-induced monocyte adhesion to vascular cells.
Conclusions:
- Nicardipine promotes CE catabolism and cholesterol clearance in arterial smooth muscle cells.
- Nicardipine reduces inflammatory cell adhesion, suggesting an anti-atherosclerotic mechanism.
- Findings support nicardipine's potential as an anti-atherosclerotic agent.