Mitochondrial dysfunction in uremic cardiomyopathy

作者：Taylor David; Bhandari Sunil; Seymour Anne Marie L^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2015, 308(6): F579-F587.

DOI：10.1152/ajprenal.00442.2014

• uremic cardiomyopathy
• mitochondrial dysfunction
• mitochondrial permeability transition pore
• chronic kidney disease

Uremic cardiomyopathy (UCM) is characterized by metabolic remodelling, compromised energetics, and loss of insulin-mediated cardioprotection, which result in unsustainable adaptations and heart failure. However, the role of mitochondria and the susceptibility of mitochondrial permeability transition pore (mPTP) formation in ischemia-reperfusion injury (IRI) in UCM are unknown. Using a rat model of chronic uremia, we investigated the oxidative capacity of mitochondria in UCM and their sensitivity to ischemia-reperfusion mimetic oxidant and calcium stressors to assess the susceptibility to mPTP formation. Uremic animals exhibited a 45% reduction in creatinine clearance (P < 0.01), and cardiac mitochondria demonstrated uncoupling with increased state 4 respiration. Following IRI, uremic mitochondria exhibited a 58% increase in state 4 respiration (P < 0.05), with an overall reduction in respiratory control ratio (P < 0.01). Cardiomyocytes from uremic animals displayed a 30% greater vulnerability to oxidant-induced cell death determined by FAD autofluorescence (P < 0.05) and reduced mitochondrial redox state on exposure to 200 mu M H2O2 (P < 0.01). The susceptibility to calcium-induced permeability transition showed that maximum rates of depolarization were enhanced in uremia by 79%. These results demonstrate that mitochondrial respiration in the uremic heart is chronically uncoupled. Cardiomyocytes in UCM are characterized by a more oxidized mitochondrial network, with greater susceptibility to oxidant-induced cell death and enhanced vulnerability to calcium-induced mPTP formation. Collectively, these findings indicate that mitochondrial function is compromised in UCM with increased vulnerability to calcium and oxidant-induced stressors, which may underpin the enhanced predisposition to IRI in the uremic heart.

• 出版日期2015-3-15