Abstract 230: Specific Mitochondrial Adaptation In Chronic Hypoxic Hearts Results In An Improved Intrinsic Energetic Homeostasis
Hypoxic states of the cardiovascular system are often associated with severe cardiac diseases. In spite of impairments in contractile activity, mitochondrial content, cell energy status and calcium transients, we recently demonstrated an improved energy homeostasis in chronic hypoxic hearts explained by a higher mitochondrial sensitivity to ATP/PCr changes, based on combined 31P-NMR spectroscopy and the analytical framework of metabolic control analysis.
In the present study, we describe the role of calcium in co-variations in cellular energy status (PCr, ATP) and cardiac work (RPP), in perfused hearts from mice adapted for three weeks to a simulated altitude of 5500 m in a barochamber.
Under basal conditions, lower cardiac work and PCr concentration confirmed energetic impairments in chronic hypoxic hearts. At high calcium concentration, cardiac work increased by 40% both in control and hypoxic hearts while a smaller PCr drop in hypoxic hearts, indicating an improved energy homeostasis and higher mitochondrial sensitivity to PCr changes. Stimulating calcium transients by adrenaline and thereby parallel activation of supply and demand components increased cardiac work twice as much only in control hearts (RPP +100%) without any significant PCr variation. The blunted effect of adrenaline in hypoxic hearts is likely the consequence of attenuated ß1-adrenergic receptors stimulation. Inhibition of mitochondrial calcium uniporter by ruthenium red which abolished the mitochondrial-mediated adrenergic regulation was not effective in chronic hearts in contrast of control.
We conclude that although chronic hypoxic hearts failed to use calcium transients to optimize their inotropic response to a specific adrenergic stimulation, they present specific adaptation of the energetic homeostasis based on improved energy supply sensitivity. Interestingly this better regulation of the energetic system is not explained by a direct effect of calcium on mitochondria but rather by an optimized metabolic feedback.
- © 2013 by American Heart Association, Inc.