Mercer 2013 Abstract IOC75

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Mitochondrial bioenergetics and therapeutic intervention in vascular disease

John Mercer, University of Cambridge, Division of Cardiovascular Medicine, Addenbrookes Hospital, Cambridge, CB2 2QQ


Abstract

Cardiovascular disease remains the commonest form of mortality and morbidity in the Western World. It accounts for more deaths than the combined incidence of all cancers. There remains an urgency to identify and translate therapies to reduce the effects of this disease and its associated co-morbidities.

Atherosclerotic disease accounts for over two thirds of all cardiovascular related deaths. Arterial vessel wall plaques rupture and cause death due to loss of integrity of the overlaying vascular smooth muscle cell (VSMC) cap. Although atheromatous plaques contain a heterogeneous pool of different cell types it is the VSMCs that by their nature are responsible for rupture as the primary source of extracellular matrix and collagen. These protein products provide the synthetic and structural stability of the cap. It has been suggested that loss of viability and vitality of these cells contributes to plaque vulnerability and rupture.

While DNA damage has long been associated with atherosclerotic plaques only relatively recently has the contribution of mitochondrial DNA damage been suggested to play a role. The mitochondrial respiratory chain is a source of ATP that the cell requires for all its energetic functions but is also a source of free radicals that produce reactive species (RS). While these RS exacerbate DNA damage and attack lipids and proteins, it is the loss of ATP that may ultimately be more detrimental. Therapeutic intervention for mitochondria dysfunction is one route on alleviating this burden. Finding alternative sources of ATP synthesis by energetic reconfiguration may also provide a vital link in delaying the kinetics of plaque rupture.


References

Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Gorenne I, Kumar S, Gray K, Figg N, Yu H, Mercer J, Bennett M. Circulation. 2013 Jan 22;127(3):386-96.

The methyl xanthine caffeine inhibits DNA damage signaling and reactive species and reduces atherosclerosis in ApoE(-/-) mice. Mercer JR, Gray K, Figg N, Kumar S, Bennett MR. Arterioscler Thromb Vasc Biol. 2012 Oct;32(10):2461-7.

Mitochondria in vascular disease. Yu E, Mercer J, Bennett M. Cardiovasc Res. 2012 Jul 15;95(2):173-82.

The mitochondria-targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+/-/ApoE-/- mice. Mercer JR, Yu E, Figg N, Cheng KK, Prime TA, Griffin JL, Masoodi M, Vidal-Puig A, Murphy MP, Bennett MR. Free Radic Biol Med. 2012 Mar 1;52(5):841-9.

DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome. Mercer JR, Cheng KK, Figg N, Gorenne I, Mahmoudi M, Griffin J, Vidal-Puig A, Logan A, Murphy MP, Bennett M. Circ Res. 2010 Oct 15;107(8):1021-31.


|keywords=Cardiovascular disease, Atherosclerosis, plaque, vascular smooth muscle cells }}

Labels:

Stress:RONS; Oxidative Stress"RONS; Oxidative Stress" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., Aging; Senescence"Aging; Senescence" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property.  Organism: Human, Mouse 

Preparation: Permeabilized cells, Permeabilized tissue, Isolated Mitochondria"Isolated Mitochondria" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property.  Enzyme: Complex I  Regulation: Aerobic and Anaerobic Metabolism"Aerobic and Anaerobic Metabolism" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property.  Coupling state: OXPHOS 

HRR: Oxygraph-2k, pH 




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