Therapy to reduce risk of coronary heart disease

Rader, Daniel J.

doi:10.1002/clc.4960260103

Cited by 13 publications

(7 citation statements)

References 33 publications

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“…1) (1). Large scale randomized clinical trials have shown that statins provide benefits in prevention of both primary and secondary cardiovascular diseases (2)(3)(4)(5)(6). However, the striking benefit achieved with statin treatment in patients with a dynamic range of cholesterol levels suggested that effects other than lipid-lowering may also contribute to these beneficial effects observed clinically.…”

mentioning

confidence: 92%

3-Hydroxyl-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitor (Statin)-induced 28-kDa Interleukin-1β Interferes with Mature IL-1β Signaling

Davaro

Forde

Garfield

et al. 2014

Journal of Biological Chemistry

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Background: HMG-CoA reductase inhibitors (statins) have anti-inflammatory effects, the molecular mechanisms of which remain unclear. Results: Statin treatment of macrophages induces secretion of a 28-kDa form of IL-1␤ that interferes with mature IL-1␤ signaling. Conclusion: Statins may dampen inflammation through induction of an anti-inflammatory form of IL-1␤. Significance: These observations may provide clues toward elucidating the in vivo anti-inflammatory effects of statins.

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confidence: 92%

3-Hydroxyl-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitor (Statin)-induced 28-kDa Interleukin-1β Interferes with Mature IL-1β Signaling

Davaro

Forde

Garfield

et al. 2014

Journal of Biological Chemistry

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“…Statins [3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitors] are potent cholesterol‐lowering drugs used for the treatment of hypercholesterolaemia (Stein 2002) and coronary heart disease (Rader 2003). In addition, statins reduce stroke incidence and may also reduce the risk of Alzheimer's disease (Hess et al .…”

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confidence: 99%

Neuroprotective effects of atorvastatin against glutamate‐induced excitotoxicity in primary cortical neurones

Bösel

Gandor

Harms

et al. 2005

Journal of Neurochemistry

189

122

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Statins [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors] exert cholesterol-independent pleiotropic effects that include anti-thrombotic, anti-inflammatory, and antioxidative properties. Here, we examined direct protective effects of atorvastatin on neurones in different cell damage models in vitro. Primary cortical neurones were pre-treated with atorvastatin and then exposed to (i) glutamate, (ii) oxygenglucose deprivation or (iii) several apoptosis-inducing compounds. Atorvastatin significantly protected from glutamate-induced excitotoxicity as evidenced by propidium iodide staining, nuclear morphology, release of lactate dehydrogenase, and mitochondrial tetrazolium metabolism, but not from oxygen-glucose deprivation or apoptotic cell death. This antiexcitototoxic effect was evident with 2-4 days pre-treatment but not with daily administration or shorter-term pre-treatment. The protective properties occurred independently of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition because co-treatment with mevalonate or other isoprenoids did not reverse or attenuate neuroprotection. Atorvastatin attenuated the glutamate-induced increase of intracellular calcium, which was associated with a modulation of NMDA receptor function. Taken together, atorvastatin exerts specific anti-excitotoxic effects independent of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition, which has potential therapeutic implications.

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“…In large clinical trials, it has been shown that the use of statins not only reduces coronary events, but also total mortality rates in patients with coronary heart disease (35)(36)(37)(38)(39)(40). Because the benefit of such a treatment is greater than expected in terms of the reduction of low density lipoprotein cholesterol levels produced, it has been proposed that statins exert actions beyond that of simply lowering cholesterol.…”

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confidence: 99%

Geranylgeraniol Regulates Negatively Caspase-1 Autoprocessing: Implication in the Th1 Response against Mycobacterium tuberculosis

Montero

Matilla

Gómez-Mampaso

et al. 2004

The Journal of Immunology

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Caspase-1 is a cysteine protease composed by two 20-kDa and two 10-kDa subunits that processes pro-IL-1β and pro-IL-18 to their mature forms. This enzyme is present in cells as a latent zymogen that becomes active through a tightly regulated proteolytic cascade. Activation is initiated by the oligomerization of an adaptor molecule, or by the formation of a multiprotein complex named inflammasome. Negative regulation of caspase-1 activation is exerted by proteins that compete with the adaptor molecule or with the inflammasome formation. We previously reported that fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, increases caspase-1 activity in PBMC. This effect was strengthened by Mycobacterium tuberculosis, rending an exacerbated IL-1β, IL-18, and IFN-γ production. Mevalonate, the product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, is a precursor for both nonsterol isoprenoid and sterol formation. In this study, we studied the involvement of mevalonate derivatives in the regulation of caspase-1 activation. Inhibition of sterol formation by SKF-104976 or haloperidol had no effect on IL-1β release. However, the isoprenoid geranylgeraniol prevented both caspase-1 activation and the exacerbated IL production induced by fluvastatin. This isoprenoid significantly reduced the release of IL-18 and IFN-γ by PBMC treated with mycobacteria, even in the absence of fluvastatin. In correlation with the increased caspase-1 activity, fluvastatin stimulated the proforms cleavage, enhancing the formation of active subunit p10. Geranylgeraniol not only prevented this effect, but induced proforms accumulation. Present results suggest that, once the proteolytic cascade is initiated, geranylgeraniol may exert an additional negative regulation on caspase-1 cleavage process.

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Therapy to reduce risk of coronary heart disease

Cited by 13 publications

References 33 publications

3-Hydroxyl-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitor (Statin)-induced 28-kDa Interleukin-1β Interferes with Mature IL-1β Signaling

3-Hydroxyl-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitor (Statin)-induced 28-kDa Interleukin-1β Interferes with Mature IL-1β Signaling

Neuroprotective effects of atorvastatin against glutamate‐induced excitotoxicity in primary cortical neurones

Geranylgeraniol Regulates Negatively Caspase-1 Autoprocessing: Implication in the Th1 Response against Mycobacterium tuberculosis

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