Avram 2019 MiP2019

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Vlad Avram
Cell-permeable succinate bypasses statin-induced decrease in mitochondrial ATP-generating respiration in human platelets.

Link: MiP2019

Avram VF, Aasander Frostner E, Ehinger J, Timar RZ, Muntean DM, Elmer E (2019)

Event: MiP2019

COST Action MitoEAGLE

Statins are the first line of treatment for the lipid disorders such as atherosclerotic disease with a class IA level of evidence, according to the new ESC guidelines [1]. Mitochondrial dysfunction plays a central role among the pathophysiological mechanisms of the statin-related side effects [2]. Furthermore, a decrease in NADH-linked respiration has been reported in permeabilized (but not intact) platelets harvested from patients that underwent a short-term statin regimen [3]. Succinate could be used to correct this metabolic dysfunction, however it displays limited cellular uptake. In the past, similar impairment of NADH-supported respiration has been by-passed using cell-permeable succinate prodrugs [4].

The present study was purported to assess the effects of three statins on mitochondrial respiration in both intact and permeabilized human platelets. Furthermore, respiration in intact platelets exposed to toxic concentrations of two of the statins were assessed both in the presence and absence of the cell-permeable succinate NV-118.

To this aim peripheral blood platelets were isolated from healthy volunteers by differential centrifugations (using K2-EDTA as anticoagulant). Respiratory capacities of intact and permeabilized cells (200 x 106 cells/mL) were analyzed using the substrate-uncoupler-inhibitor titration protocols following acute incubation with increasing doses of simvastatin, atorvastatin and cerivastatin. Platelet permeabilization was achieved by adding digitonin after which a sequential addition of complex-specific respiratory substrates and inhibitors with or without NV-118 was performed. NV-118 was generously provided by NeuroVive Pharmaceutical AB (Lund, Sweden), also available in the MitoKit-CII from Oroboros Instruments GmbH Innsbruck, Austria.

All three statins presented a dose-dependent reduction of ET-capacity and NADH-linked OXPHOS. Moreover, increased non-ATP-generating (dyscoupled) respiration was found with the two statins. The combination of ETS inhibition and dyscoupling effect additively converged to abolish coupled respiration. NV-118 was used to increase the ATP-generating respiration in intact platelets exposed to a toxic concentration of either cerivastatin or atorvastatin.

Cell-permeable succinate NV118 bypasses statin induced mitochondrial dysfunction. Whether cell-permeable succinate prodrugs can be used to alleviate statin-induced mitochondrial dysfunction in patients chronically treated with statins certainly warrants further investigation.

Keywords: Mitochondria, Statin, Platelets, Respiratory dysfunction, Cell-permeable succinate Bioblast editor: Plangger M, Tindle-Solomon L O2k-Network Lab: RO Timisoara Muntean DM, SE Lund Elmer E


Labels: MiParea: Respiration, Pharmacology;toxicology 


Organism: Human  Tissue;cell: Platelet  Preparation: Permeabilized cells, Intact cells 



HRR: Oxygraph-2k 

Metformin 

Affiliations

Avram VF(1,2), Åsander Frostner E(3,4), Ehinger J(3), Timar RZ(1), Muntean DM(2,*), Elmér E(3,5)
  1. Dept Internal Medicine – Diabetes Nutrition Metabolic Diseases, County Emergency Hospital "Pius Brînzeu" Timișoara
  2. Dept Functional Sciences - Pathophysiology, *Centre Translational Research Systems Medicine; "Victor Babeș" Univ Medicine Pharmacy, Timișoara, Romania
  3. Dept Clinical Sciences, Mitochondrial Medicine, Lund Univ
  4. NeuroVive Pharmaceutical AB, Medicon Village
  5. Skane Univ Hospital, Clinical Neurophysiology; Lund, Sweden

Figures

Avram Figure1 MiP2019.jpg

Figure 1: Dose-dependent statin-induced mitochondrial dysfunction.





Avram Figure2 MiP2019.jpg

Figure 2: Oxygen consumption of intact platelets exposed (green) or not (red) to statins in the presence of NV-118.







References

  1. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Lale Tokgozoglu L, Wiklund O (2019) ESC Scientific Document Group, 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J https://doi.org/10.1093/eurheartj/ehz455
  2. Vevera J, Fišar Z, Nekovářová T, Vrablík M, Zlatohlávek L, Hroudová J, Singh N, Raboch J, Valeš K (2016) Statin-induced changes in mitochondrial respiration in blood platelets in rats and humans with dyslipidemia. Physiol Res 65:777-88.
  3. Piel S, Ehinger JK, Elmer E, Hansson MJ (2013) Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial Complex I inhibition. Acta Physiol (Oxf) 213:171-80.