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Improved energy supply regulation in chronic hypoxic mouse counteracts hypoxia-induced altered cardiac energetics.

Calmettes G, Deschodt-Arsac V, Gouspillou G, Miraux S, Muller B, Franconi JM, Thiaudiere E, Diolez P - PLoS ONE (2010)

Bottom Line: Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged.This higher elasticity induces an improved response of energy supply to cellular energy demand.The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Résonance Magnétique des Systèmes Biologiques, UMR 5536 CNRS Université Bordeaux 2, Bordeaux, France. guillaume.calmettes@rmsb.u-bordeaux2.fr

ABSTRACT

Background: Hypoxic states of the cardiovacular system are undoubtedly associated with the most frequent diseases of modern time. Therefore, understanding hypoxic resistance encountered after physiological adaptation such as chronic hypoxia, is crucial to better deal with hypoxic insult. In this study, we examine the role of energetic modifications induced by chronic hypoxia (CH) in the higher tolerance to oxygen deprivation.

Methodology/principal findings: Swiss mice were exposed to a simulated altitude of 5500 m in a barochamber for 21 days. Isolated perfused hearts were used to study the effects of a decreased oxygen concentration in the perfusate on contractile performance (RPP) and phosphocreatine (PCr) concentration (assessed by (31)P-NMR), and to describe the integrated changes in cardiac energetics regulation by using Modular Control Analysis (MoCA). Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged. MoCA demonstrated that this adaptation to hypoxia is the direct consequence of the higher responsiveness (elasticity) of ATP production of CH hearts compared with Controls (-1.88+/-0.38 vs -0.89+/-0.41, p<0.01) measured under low oxygen perfusion. This higher elasticity induces an improved response of energy supply to cellular energy demand. The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.

Conclusions/significance: As suggested by the present study, the mechanisms responsible for this increase in elasticity and the consequent improved ability of CH heart metabolism to respond to oxygen deprivation could participate to limit the damages induced by hypoxia.

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Related in: MedlinePlus

Modular Regulation Analysis of the effects of the decrease in oxygen availability on Control (A) and CH (B) mouse hearts.The size of the arrows is proportional to the effect of the decrease in oxygen availability, and the figures represent the effect expressed as % change from starting condition (high oxygen).
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pone-0009306-g002: Modular Regulation Analysis of the effects of the decrease in oxygen availability on Control (A) and CH (B) mouse hearts.The size of the arrows is proportional to the effect of the decrease in oxygen availability, and the figures represent the effect expressed as % change from starting condition (high oxygen).

Mentions: The application of Modular Regulation Analysis [22], [26] allows to quantify how decreasing oxygen availability triggers these changes in cardiac energetics in Control and CH hearts (see Text S1 for calculus). Results are presented in figure 2 both for Control (A) and CH (B) hearts. As described above, the total effect of low oxygen on Control hearts bioenergetics was a decrease of 46.2% in RPP, associated with a 23.4% decrease in [PCr] (figure 1B). This decrease by half of the contractile activity of the system is the consequence of two distinct effects induced by acute hypoxia on each module: (i) a direct effect of the decrease in oxygen on energy supply and demand, and (ii) an additional indirect effect on each module in response to the observed change in PCr concentration. Calculation of direct effect shows that decreasing oxygen availability strongly inhibits energy supply directly (−85.5% in our conditions) whereas energy demand is not affected (+1.5%) (figure 2A). These effects are responsible for the drop in PCr concentration (−23.4%), which in turn causes indirect effects on both modules, depending on their respective elasticities to changes in PCr. Thus, this drop in PCr induces a strong positive effect on energy-supply (+39.3%), that compensate in part for the strong direct negative effect induced by acute hypoxia on this module, and a strong negative effect on energy-demand (−47.7%) (figure 2A). The last information obtained from regulation analysis is the global response of heart contractile activity to the decrease in oxygen through each module. This global effect depends on the control coefficients and therefore quantifies how strongly the decrease in oxygen availability acts on the system through each module. Here, alteration induced by oxygen shortage on heart energetics essentially comes from energy supply inhibition with a global effect of −46.9% on contraction, whereas no effect is measured from energy demand (+0.7%) (figure 2A).


Improved energy supply regulation in chronic hypoxic mouse counteracts hypoxia-induced altered cardiac energetics.

Calmettes G, Deschodt-Arsac V, Gouspillou G, Miraux S, Muller B, Franconi JM, Thiaudiere E, Diolez P - PLoS ONE (2010)

Modular Regulation Analysis of the effects of the decrease in oxygen availability on Control (A) and CH (B) mouse hearts.The size of the arrows is proportional to the effect of the decrease in oxygen availability, and the figures represent the effect expressed as % change from starting condition (high oxygen).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2823784&req=5

pone-0009306-g002: Modular Regulation Analysis of the effects of the decrease in oxygen availability on Control (A) and CH (B) mouse hearts.The size of the arrows is proportional to the effect of the decrease in oxygen availability, and the figures represent the effect expressed as % change from starting condition (high oxygen).
Mentions: The application of Modular Regulation Analysis [22], [26] allows to quantify how decreasing oxygen availability triggers these changes in cardiac energetics in Control and CH hearts (see Text S1 for calculus). Results are presented in figure 2 both for Control (A) and CH (B) hearts. As described above, the total effect of low oxygen on Control hearts bioenergetics was a decrease of 46.2% in RPP, associated with a 23.4% decrease in [PCr] (figure 1B). This decrease by half of the contractile activity of the system is the consequence of two distinct effects induced by acute hypoxia on each module: (i) a direct effect of the decrease in oxygen on energy supply and demand, and (ii) an additional indirect effect on each module in response to the observed change in PCr concentration. Calculation of direct effect shows that decreasing oxygen availability strongly inhibits energy supply directly (−85.5% in our conditions) whereas energy demand is not affected (+1.5%) (figure 2A). These effects are responsible for the drop in PCr concentration (−23.4%), which in turn causes indirect effects on both modules, depending on their respective elasticities to changes in PCr. Thus, this drop in PCr induces a strong positive effect on energy-supply (+39.3%), that compensate in part for the strong direct negative effect induced by acute hypoxia on this module, and a strong negative effect on energy-demand (−47.7%) (figure 2A). The last information obtained from regulation analysis is the global response of heart contractile activity to the decrease in oxygen through each module. This global effect depends on the control coefficients and therefore quantifies how strongly the decrease in oxygen availability acts on the system through each module. Here, alteration induced by oxygen shortage on heart energetics essentially comes from energy supply inhibition with a global effect of −46.9% on contraction, whereas no effect is measured from energy demand (+0.7%) (figure 2A).

Bottom Line: Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged.This higher elasticity induces an improved response of energy supply to cellular energy demand.The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Résonance Magnétique des Systèmes Biologiques, UMR 5536 CNRS Université Bordeaux 2, Bordeaux, France. guillaume.calmettes@rmsb.u-bordeaux2.fr

ABSTRACT

Background: Hypoxic states of the cardiovacular system are undoubtedly associated with the most frequent diseases of modern time. Therefore, understanding hypoxic resistance encountered after physiological adaptation such as chronic hypoxia, is crucial to better deal with hypoxic insult. In this study, we examine the role of energetic modifications induced by chronic hypoxia (CH) in the higher tolerance to oxygen deprivation.

Methodology/principal findings: Swiss mice were exposed to a simulated altitude of 5500 m in a barochamber for 21 days. Isolated perfused hearts were used to study the effects of a decreased oxygen concentration in the perfusate on contractile performance (RPP) and phosphocreatine (PCr) concentration (assessed by (31)P-NMR), and to describe the integrated changes in cardiac energetics regulation by using Modular Control Analysis (MoCA). Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged. MoCA demonstrated that this adaptation to hypoxia is the direct consequence of the higher responsiveness (elasticity) of ATP production of CH hearts compared with Controls (-1.88+/-0.38 vs -0.89+/-0.41, p<0.01) measured under low oxygen perfusion. This higher elasticity induces an improved response of energy supply to cellular energy demand. The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.

Conclusions/significance: As suggested by the present study, the mechanisms responsible for this increase in elasticity and the consequent improved ability of CH heart metabolism to respond to oxygen deprivation could participate to limit the damages induced by hypoxia.

Show MeSH
Related in: MedlinePlus