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Effect of statins on the proteasomal activity in mammalian endothelial and vascular smooth muscle cells
Antje Ludwig1, Britt Friedel, Susanne Metzkow
1Medizinische Klinik und Poliklinik, Schwerpunkt Kardiologie, Angiologie, Pneumologie Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
Insights
Statins, used to lower cholesterol, share some effects with proteasome inhibitors on vascular cells. However, studies show statins do not inhibit proteasome activity, indicating different mechanisms of action.
Area of Science:
- Cardiovascular Pharmacology
- Cell Biology
- Biochemistry
Background:
- Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) prevent cardiovascular events and possess pleiotropic effects.
- Statin-induced pleiotropic effects in vascular cells resemble those of proteasome inhibitors.
- A hypothesis suggests statins may target the proteasome for some of their effects.
Purpose of the Study:
- To investigate whether statins modulate proteasomal activity in vascular cells.
- To compare the effects of specific statins (simvastatin, atorvastatin, pravastatin) with a proteasome inhibitor (clasto-lactacystin).
- To determine if shared biological effects stem from a common mechanism on proteasome activity.
Main Methods:
- Studied effects on morphology, proliferation, and viability in endothelial (CPAE, Ea.hy962) and vascular smooth muscle cells (VSMCs).
- Assessed proteasomal activity in cell extracts and purified human 20S proteasomes after treatment.
- Investigated the role of mevalonic acid in reversing statin-induced effects.
Main Results:
- Statins and lactacystin induced similar morphological changes and reduced proliferation in CPAE cells.
- Statin effects were reversible by mevalonic acid; lactacystin effects were not.
- Lactacystin significantly reduced proteasomal activity, while statins did not alter activity in any cell type tested.
- High doses of statins did not affect purified human 20S proteasome activity.
Conclusions:
- The observed similarities in biological effects between statins and proteasome inhibitors in vascular cells are not due to direct proteasome inhibition by statins.
- Statins and proteasome inhibitors likely exert their comparable effects through distinct molecular pathways.
- This research clarifies the mechanism of statin action, differentiating it from proteasome inhibition.
Abstract:
Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, known as statins, effectively prevent cardiovascular events. In addition to their lipid lowering properties, a variety of pleiotropic effects on cardiovascular cells were demonstrated in vitro and in vivo. It has been hypothized that statins deploy a part of their effects by targeting the proteasome. Statin-induced effects remarkably overlap with effects obtained by inhibition of the proteasome in endothelial and vascular smooth muscle cells (e.g., endothelial nitric oxide synthase (eNOS)-upregulation, attenuation of nuclear factor kappa B (NF-kappaB) activation, inhibition of proliferation). We therefore examined, whether statins modulate the proteasomal activity of vascular cells. We studied the effect of simvastatin, atorvastatin, and pravastatin as well as of the proteasome inhibitor clasto-lactacystin on morphology, proliferation, viability, and proteasomal activity in two mammalian endothelial cell lines (CPAE and Ea.hy962), and in primary vascular smooth muscle cells (VSMCs). Both statins and lactacystin induced comparable morphological changes and attenuated proliferation of calf pulmonary artery cell line (CPAE). Whereas the statin-induced effects were reversed by mevalonic acid, however, the lactacystin-induced alterations were not influenced by mevalonic acid. As expected, lactacystin caused a significant loss of proteasomal activity measured in the extract of treated CPAE cells, whereas the extracts of statin-treated CPAEs exhibited unchanged activities. This result was also confirmed in Ea.hy926 cells and in primary rat VSMCs. We show here, that even high doses of statins do not modulate the activities of purified human 20S proteasomes. We conclude that the similar biological effects of statins and proteasome inhibitors in vascular cells are not due to a common inhibitory mechanism of action on the proteasome.
