Cardiac metabolic adaptations in response to chronic hypoxia

Abstract

Since a constant supply of oxygen is essential to sustain life, organisms have evolved multiple defence mechanisms to ensure maintenance of the delicate balance between oxygen supply and demand. However, this homeostatic balance is perturbed in response to a severe impairment of oxygen supply, thereby activating maladaptive signalling cascades that result in cardiac damage. Past research efforts have largely focused on determining the pathophysiological effects of severe lack of oxygen. By contrast, and as reviewed here, exposure to moderate chronic hypoxia may induce cardioprotective properties. The hypothesis put forward is that chronic hypoxia triggers regulatory pathways that mediate long-term cardiac metabolic remodelling, particularly at the transcriptional level. The novel proposal is that exposure to chronic hypoxia triggers (a) oxygen-sensitive transcriptional modulators that induce a switch to increased carbohydrate metabolism (fetal gene programme) and (b) enhanced mitochondrial respiratory capacity to sustain and increase efficiency of mitochondrial energy production. These compensatory protective mechanisms preserve contractile function despite hypoxia.

Figure 1

Delicate balance between oxygen supply and demand Physiological hypoxia triggers various defence mechanisms, for e.g. erythropoiesis and angiogenesis to increase red blood cell mass and oxygen delivery to the heart. Adaptive cardiac metabolic remodelling (switch to greater carbohydrate versus fatty acid utilization) is also proposed to play a key role in hypoxia-mediated cardioprotection. Disruption of this homeostatic balance (pathophysiological hypoxia) may overwhelm an organism's defence machinery, triggering maladaptive signalling cascades that result in myocardial damage.

Figure 2

Cardiac metabolic gene remodelling in response to chronic hypoxia It is proposed that ROS relay extracellular signals to the transcriptional machinery to initiate adaptive cardiac metabolic remodelling. HIF-1α (in reduced state) heterodimerizes with HIF-1β and subsequently binds to hypoxia-response elements (HRE) within the promoter region to increase expression of glucose metabolic genes. Hypoxia-mediated mRNA stabilization may also increase steady-state levels of glucose metabolic gene transcripts. Altered OH^• levels are proposed to decrease PPARα and RXRα (in reduced state) by increased proteasomal degradation, leading to reduced binding to PPAR response elements (PPRE) within the promoter region and lower expression of fatty acid metabolic genes.

Figure 3

Mitochondria integrate signalling cascades and transcriptional circuits in response to chronic hypoxia It is proposed that physiological ROS generated during moderate chronic hypoxia modulate Ca²⁺ signalling and transcriptional pathways to enhance cardioprotection in response to severe biological stress. Firstly, ROS activate Ca²⁺–calmodulin-dependent protein kinase (CaMK) to increase expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis. Secondly, co-localization between mitochondria and the endoplasmic reticulum facilitates mitochondrial Ca²⁺ uptake, thereby accelerating enzyme activities of Krebs cycle dehydrogenases. Thirdly, moderate chronic hypoxia enhances tolerance of myocardial mitochondria to Ca²⁺ overload, thereby lowering the probability of mitochondrial permeability transition pore (mPTP) opening. Together these steps are proposed to enhance mitochondrial energy production and attenuate cell death in the heart when challenged by stress for, for example, severe oxygen deprivation.