Mitochondrial bioenergetics and therapeutic intervention in cardiovascular disease

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• 作者：John R. Mercer
• 关键词：Vascular smooth muscle cell ; Mitochondria ; Energetic ; Fluxomics ; TALENS ; Heteroplasmy
• 刊名：Pharmacology and Therapeutics
• 出版年：January, 2014
• 年：2014
• 卷：141
• 期：1
• 页码：13-20
• 全文大小：627 K

文摘

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 plaques contain a heterogeneous pool of different cell types, it is the VSMCs that by their nature are responsible for rupture. VSMC are the primary source of extracellular matrix and collagen and 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.