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Atherosclerosis, cell motility, calcium, and calcium-channel blockers
1Department of Research, University Hospitals, Basel, Switzerland.
Insights
Calcium-channel blockers can correct early atherosclerosis development by interfering with platelet and vascular smooth muscle cell activation. These blockers impact cellular signaling and gene activation, offering a therapeutic avenue for atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- Early atherosclerosis involves complex humoral-cellular interactions.
- Platelet-activating factors, low-density lipoprotein (LDL), and platelet-derived growth factor play key roles.
- These factors activate platelets and vascular smooth muscle cells, contributing to disease progression.
Purpose of the Study:
- To elucidate the mechanisms by which key molecular players drive early atherosclerosis.
- To investigate the potential of calcium-channel blockers in mitigating these cellular and molecular events.
Main Methods:
- Analysis of cellular signaling pathways involving phospholipase C and phosphoinositides.
- Assessment of LDL's action on platelet aggregation and vascular smooth muscle cell proliferation.
- Evaluation of platelet-derived growth factor's effect on LDL-receptor and HMG-CoA reductase gene transcription.
- Examination of calcium-channel antagonists' impact on these processes.
Main Results:
- Platelet-activating factors increase cytosolic calcium and induce platelet aggregation and secretion.
- LDL mimics hormone action, promoting platelet aggregation and smooth muscle cell proliferation, effects reduced by high-density lipoproteins.
- Platelet-derived growth factor stimulates LDL-receptor and HMG-CoA reductase gene transcription.
- Calcium-channel antagonists inhibit HMG-CoA reductase gene transcription and interfere with stimulus-response coupling via membrane actions and gene activation interference.
Conclusions:
- Calcium-channel blockers offer a therapeutic strategy for early atherosclerosis by modulating key cellular interactions.
- These drugs interfere with stimulus-response coupling through multiple mechanisms, including calcium influx inhibition and gene activation modulation.
Abstract:
Three key players in the humoral-cellular interactions that occur during the early development of atherosclerosis are presented as they activate platelets and vascular smooth muscle cells but eventually can be corrected by calcium-channel blockers. Platelet-activating factors via phospholipase C and phosphoinositides increase cytosolic calcium and phosphorylate contractile proteins, thereby inducing a change--aggregation and the secretory response of platelets. Low-density lipoprotein (LDL) has a similar hormone-like action and activates the signal transfer cascade that eventually leads to platelet aggregation as well as vascular smooth muscle cell proliferation. These effects can be greatly reduced by high-density lipoproteins. Platelet-derived growth factor stimulates the transcription of the LDL-receptor gene as well as the HMG-CoA reductase gene. The latter is inhibited by calcium-channel antagonists while the former is further enhanced. Thus, calcium-channel antagonists interfere with the stimulus-response coupling not only via slow calcium-channel influx inhibition but also by an additional membrane action and interference with gene activation.