New possible pharmacological targets for statins and ezetimibe

Niedzielski, Mateusz; Broncel, Marlena; Gorzelak-Pabiś, Paulina; Woźniak, Ewelina

doi:10.1016/j.biopha.2020.110388

Cited by 42 publications

(27 citation statements)

References 43 publications

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“…Since statins can protect the endothelium, they can potentially suppress the harmful effect of coronavirus. Clearly, these drugs have a range of beneficial effects on the vascular endothelium, independent of their hypolipidemic effect [6].…”

Section: Statins Improve Endothelial Functionsmentioning

confidence: 99%

“…These results may be caused by the pleiotropic activity of statins, and recent studies suggest various mechanisms that may directly affect SARS-CoV-2 endocytosis (ACE2), replication (main protease and RNA polymerase) or indirect mechanisms unrelated to coronavirus infection, such as e.g., anti-inflammatory, anti-coagulant effects or endothelial function improvement [6][7][8][9][10][11]. In addition, it is very likely that the direct effect on the ACE2 receptor could be of particular importance for the new British coronavirus strain, possibly due to the stronger interaction between the spike protein and the ACE2 receptor [12].…”

Section: Introductionmentioning

confidence: 99%

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COVID-19: Direct and Indirect Mechanisms of Statins

Pawlos

Niedzielski

Gorzelak-Pabiś

et al. 2021

IJMS

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The virus responsible for the current COVID-19 pandemic is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a new virus with high infectivity and moderate mortality. The major clinical manifestation of COVID-19 is interstitial pneumonia, which may progress to acute respiratory distress syndrome (ARDS). However, the disease causes a potent systemic hyperin-flammatory response, i.e., a cytokine storm or macrophage activation syndrome (MAS), which is associated with thrombotic complications. The complexity of the disease requires appropriate intensive treatment. One of promising treatment is statin administration, these being 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that exert pleiotropic anti-inflammatory effects. Recent studies indicate that statin therapy is associated with decreased mortality in COVID-19, which may be caused by direct and indirect mechanisms. According to literature data, statins can limit SARS-CoV-2 cell entry and replication by inhibiting the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The cytokine storm can be ameliorated by lowering serum IL-6 levels; this can be achieved by inhibiting Toll-like receptor 4 (TLR4) and modulating macrophage activity. Statins can also reduce the complications of COVID-19, such as thrombosis and pulmonary fibrosis, by reducing serum PAI-1 levels, attenuating TGF-β and VEGF in lung tissue, and improving endothelial function. Despite these benefits, statin therapy may have side effects that should be considered, such as elevated creatinine kinase (CK), liver enzyme and serum glucose levels, which are already elevated in severe COVID-19 infection. The present study analyzes the latest findings regarding the benefits and limitations of statin therapy in patients with COVID-19.

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Section: Statins Improve Endothelial Functionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

COVID-19: Direct and Indirect Mechanisms of Statins

Pawlos

Niedzielski

Gorzelak-Pabiś

et al. 2021

IJMS

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“…The guidelines in high and very high-risk patients recommend high-intensity statin—atorvastatin (40–80 mg) or rosuvastatin (20–40 mg) or combination therapy ezetimibe with statins in cases of statin intolerance or insufficiency [ 9 ]. Beside the hypolipidemic effect, statins also have a pleiotropic anti-inflammatory effect, which can result in additional benefits to patients in high-risk groups [ 10 ]. Despite many studies, we still do not know whether combined treatment with statins and ezetimibe offers greater pleiotropic properties than statin monotherapy [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

A comparison of the effects of monotherapy with rosuvastatin, atorvastatin or ezetimibe versus combination treatment with rosuvastatin-ezetimibe and atorvastatin-ezetimibe on the integrity of vascular endothelial cells damaged by oxidized cholesterol

et al. 2021

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Dyslipidemia, atherosclerosis, and cardiovascular events can be prevented, or treated, using statins, alone or in combination with ezetimibe. The aim of the study was to compare the direct pleiotropic effects of two commonly-used statins (atorvastatin, rosuvastatin), ezetimibe and their combinations on endothelial cells damaged by oxidized cholesterol. HUVEC cultures were stimulated for 20 hours with atorvastatin (5 μM; 2793 ng/mL), rosuvastatin (10 μM; 4815 ng/mL), ezetimibe (1.22 μM; 500 ng/mL), atorvastatin plus ezetimibe (5 μM + 1.22 μM; 2793 ng/mL + 500 ng/mL) and rosuvastatin plus ezetimibe (10 μM + 1.22 μM; 4815 ng/mL + 500ng/mL) in separate groups, with or without 25-hydroxycholesterol pre-incubation (24.83 μM; 10 μg/mL; four hours then washout). HUVEC integrity was measured in the RTCA-DP xCELLigence system. The mRNA expression and protein levels of ZO-1, OCLN, ICAM-1 were analyzed by real-time PCR and ELISA. Pre-incubation with 25-OHC resulted in decreased endothelial cell integrity (p<0.001), decreased expression of ZO-1 mRNA (p<0.05) and protein levels (p<0.05), OCLN mRNA (p<0.05) and protein levels (p<0.05) and increased ICAM-1 mRNA (p<0.001) and protein levels (p<0.001) compared to the control group. Incubation with rosuvastatin (12h p<0.01; 24h p<0.001) and atorvastatin (only 12h p<0.05) restored HUVEC integrity. Subsequent incubation with rosuvastatin increased ZO-1 mRNA (p<0.001) and protein (p<0.001) levels. Subsequent addition of ezetimibe increased ZO-1 mRNA level (p<0.001) but not protein level. Furthermore, only incubation with rosuvastatin increased OCLN mRNA (p<0.05) and protein (p<0.05) levels. In each drug-stimulated group, both ICAM-1 mRNA and protein levels were reduced after initial incubation with oxysterol (p<0.05). 25-hydroxycholesterol disrupts endothelial integrity, decreases the mRNA and protein levels of tight junction, and increases those of intercellular adhesion molecules. Both rosuvastatin and atorvastatin can improve endothelial integrity, but only rosuvastatin can completely abolish the effect of oxysterol. The combination of statins with ezetimibe has less direct effect on the endothelial barrier than the statins alone.

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“…In the cardiovascular system, non-lipid mechanisms of statins are associated with improved endothelial function, reduced inflammation, increased fibrinolysis and plaque stability [ 3 ]. The protective effects of statins on the vascular endothelium are related to the enhanced production and bioavailability of nitric oxide (NO) as well as restoration of the redox balance [ 3 , 4 ], whereas their anti-inflammatory effects include the reduction of C-reactive protein levels, leukocyte infiltration and T cell activation [ 5 , 6 , 7 ]. Moreover, statins demonstrate a promising therapeutic potential in the field of bone tissue engineering and bone regeneration due to their ability to promote the expression of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Assessing the Interactions of Statins with Human Adenylate Kinase Isoenzyme 1: Fluorescence and Enzyme Kinetic Studies

Wujak

Kozakiewicz

Ciarkowska

et al. 2021

IJMS

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Statins are the most effective cholesterol-lowering drugs. They also exert many pleiotropic effects, including anti-cancer and cardio- and neuro-protective. Numerous nano-sized drug delivery systems were developed to enhance the therapeutic potential of statins. Studies on possible interactions between statins and human proteins could provide a deeper insight into the pleiotropic and adverse effects of these drugs. Adenylate kinase (AK) was found to regulate HDL endocytosis, cellular metabolism, cardiovascular function and neurodegeneration. In this work, we investigated interactions between human adenylate kinase isoenzyme 1 (hAK1) and atorvastatin (AVS), fluvastatin (FVS), pravastatin (PVS), rosuvastatin (RVS) and simvastatin (SVS) with fluorescence spectroscopy. The tested statins quenched the intrinsic fluorescence of hAK1 by creating stable hAK1-statin complexes with the binding constants of the order of 104 M−1. The enzyme kinetic studies revealed that statins inhibited hAK1 with significantly different efficiencies, in a noncompetitive manner. Simvastatin inhibited hAK1 with the highest yield comparable to that reported for diadenosine pentaphosphate, the only known hAK1 inhibitor. The determined AK sensitivity to statins differed markedly between short and long type AKs, suggesting an essential role of the LID domain in the AK inhibition. Our studies might open new horizons for the development of new modulators of short type AKs.

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New possible pharmacological targets for statins and ezetimibe

Cited by 42 publications

References 43 publications

COVID-19: Direct and Indirect Mechanisms of Statins

COVID-19: Direct and Indirect Mechanisms of Statins

A comparison of the effects of monotherapy with rosuvastatin, atorvastatin or ezetimibe versus combination treatment with rosuvastatin-ezetimibe and atorvastatin-ezetimibe on the integrity of vascular endothelial cells damaged by oxidized cholesterol

Assessing the Interactions of Statins with Human Adenylate Kinase Isoenzyme 1: Fluorescence and Enzyme Kinetic Studies

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