Atorvastatin affects negatively respiratory function of isolated endothelial mitochondria

Broniarek, Izabela; Jarmuszkiewicz, Wiesława

doi:10.1016/j.abb.2017.12.003

Cited by 14 publications

(13 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our previous in vitro studies have shown that acute (at high concentrations above 100 µM) direct administration of ATOR to isolated endothelial mitochondria strongly disrupts mitochondrial respiratory activity, diminishes m∆Ψ, and elevates mROS formation [21]. These effects were also found in the present study, where the influence of chronic exposure of endothelial cells to ATOR at physiological concentration (100 nM) on mitochondrial functioning may result from a direct effect on mitochondria and from inhibition of the mevalonate pathway.…”

Section: Discussionsupporting

confidence: 87%

“…Therefore, we chose the hydrophobic statin atorvastatin (ATOR) and the hydrophilic statin pravastatin (PRAV), which are not prodrugs that require activation and therefore can be used for in vitro studies. Our previous in vitro studies have shown that the acute (in high concentrations, above 100 µM) direct administration of ATOR to isolated endothelial mitochondria strongly disrupts their function, whereas hydrophilic PRAV administered directly to isolated endothelial mitochondria has no significant effect [21]. These studies did not describe the effects of statins on mitochondrial function resulting from the inhibition of the mevalonate pathway.…”

Section: Introductionmentioning

confidence: 92%

See 1 more Smart Citation

The Influence of Statins on the Aerobic Metabolism of Endothelial Cells

Broniarek

Dominiak

Gałgański

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Endothelial mitochondrial dysfunction is considered to be the main cause of cardiovascular disease. The aim of this research was to elucidate the effects of cholesterol-lowering statins on the aerobic metabolism of endothelial cells at the cellular and mitochondrial levels. In human umbilical vein endothelial cells (EA.hy926), six days of exposure to 100 nM atorvastatin (ATOR) induced a general decrease in mitochondrial respiration. No changes in mitochondrial biogenesis, cell viability, or ATP levels were observed, whereas a decrease in Coenzyme Q10 (Q10) content was accompanied by an increase in intracellular reactive oxygen species (ROS) production, although mitochondrial ROS production remained unchanged. The changes caused by 100 nM pravastatin were smaller than those caused by ATOR. The ATOR-induced changes at the respiratory chain level promoted increased mitochondrial ROS production. In addition to the reduced level of mitochondrial Q10, the activity of Complex III was decreased, and the amount of Complex III in a supercomplex with Complex IV was diminished. These changes may cause the observed decrease in mitochondrial membrane potential and an increase in Q10 reduction level as a consequence, leading to elevated mitochondrial ROS formation. The above observations highlight the role of endothelial mitochondria in response to potential metabolic adaptations related to the chronic exposure of endothelial cells to statins.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 92%

The Influence of Statins on the Aerobic Metabolism of Endothelial Cells

Broniarek

Dominiak

Gałgański

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mechanistically, we show that the inhibitory effects of atorvastatin on HBMEC are due to its ability in inhibiting mitochondrial respiration, leading to oxidative stress and damage ( Figure ). This is consistent with the previous work that atorvastatin affects negatively the mitochondrial respiratory function in human umbilical vein endothelial cells via inducing loss of mitochondrial membrane integrity, reducing maximal respiratory rate and oxidative phosphorylation efficacy [32]. Our work further demonstrates that the decreased mitochondrial respiration is likely to be due to the suppressed activities of mitochondrial complex I and II ( Figure b ).…”

Section: Discussionsupporting

confidence: 93%

Atorvastatin disrupts primary human brain microvascular endothelial cell functions via prenylation‐dependent mitochondrial inhibition and oxidative stress

Tan¹,

Yu²,

Lin³

2020

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

Primary human brain microvascular endothelial cell (HBMEC) is the major component of the blood–brain barrier (BBB). Atorvastatin, a HMG‐CoA reductase inhibitor, is a cholesterol‐lowering drug commonly used to reduce the risk for cardiovascular disease. Numerous studies have reported the pleiotropic effects of atorvastatin on endothelial cells, but the findings are controversial and inconclusive. In addition, little is known about the biological effects of atorvastatin on HBMEC. In this work, we demonstrate that atorvastatin at micromolar but not nanomolar concentrations induces dysfunctions of a number of HBMEC events, including differentiation into capillary network, migration and growth but not cell adhesion. We further show that the inhibitory effects of atorvastatin on HBMEC are independent of angiogenesis stimulators. Atorvastatin induces HBMEC apoptosis even in the presence of vascular endothelial growth factor (VEGF) and serum. Mechanism studies indicate that atorvastatin at micromolar concentration leads to protein prenylation inhibition, mitochondrial dysfunction and thereby subsequent oxidative stress and damage in HBMEC. Rescue experiments confirm that atorvastatin inhibits HBMEC functions via prenylation‐dependent mitochondrial inhibition. Our work reveals the inhibitory effects of atorvastatin on HBMEC and suggests the possible negative influence of atorvastatin in blood–brain barrier.

show abstract

“…Previous studies showed that statins interfere with calcium homeostasis to inhibit mitochondrial complexes I and III [ 27 ], and can weakly inhibit OCR in cancer cells [ 28 ]. To determine if STN could inhibit OCR in the BRAFi-resistant melanoma cells in our study, we performed Seahorse bioenergetics stress tests in A375R1 cells.…”

Section: Resultsmentioning

confidence: 99%

Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas

et al. 2022

View full text Add to dashboard Cite

Background Primary and posttreatment resistance to BRAFV600 mutation–targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)–resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy. Methods We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)–based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment. Results A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation. Conclusions STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.

show abstract

Atorvastatin affects negatively respiratory function of isolated endothelial mitochondria

Cited by 14 publications

References 43 publications

The Influence of Statins on the Aerobic Metabolism of Endothelial Cells

The Influence of Statins on the Aerobic Metabolism of Endothelial Cells

Atorvastatin disrupts primary human brain microvascular endothelial cell functions via prenylation‐dependent mitochondrial inhibition and oxidative stress

Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas

Contact Info

Product

Resources

About