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

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.

Figure 1. Energetic parameters of the perfused hearts of Control and CH mice under high and low oxygen conditions.

Representative ³¹P-NMR spectra, corresponding PCr concentrations, and contraction parameters under high and low oxygen perfusion for Control (A, B) and CH (C, D) hearts. *P<0.05 and **P<0.01 between high and low oxygen. N.S., non significantly different.

Figure 2. 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).

Figure 3. Elasticities plot of the adaptation of CH hearts to hypoxia.

Open square: elasticities of Control hearts under high oxygen condition (energy supply: −2.46±0.73, energy demand: 1.98±1.15, values obtained from [8]). Solid square: elasticities of Control hearts in low oxygen condition (energy supply: −0.89±0.41, energy demand: 2.09±0.66). Solid circles: elasticities of CH hearts in low oxygen condition (energy supply: −1.88±0.38, energy demand: 1.73±0.62). Shadowed zone indicates normal control pattern (normal distribution of the control between energy supply and demand) in mouse heart energetics, as described in .

Figure 4. Experimental protocol for the measurement of both energy supply and demand elasticities in each heart.

All measurements were performed after a 20 min stabilization period.