Metabolic Adaptations and Therapies in Cardiac Hypoxia: Mechanisms and Clinical Implications/ Potential Strategies

Abstract

Cardiac hypoxia triggers a cascade of responses and functional changes in myocardial and non-myocardial cells, profoundly affecting cellular metabolism, oxygen-sensing mechanisms, and immune responses. Myocardial cells, being the primary cell type in cardiac tissue, undergo significant alterations in energy metabolism, including glycolysis, fatty acid metabolism, ketone body utilization, and branched-chain amino acid metabolism, to maintain cardiac function under hypoxic conditions. Non-myocardial cells, such as fibroblasts, endothelial cells, and immune cells, although fewer in number, play crucial roles in regulating cardiac homeostasis, maintaining structural integrity, and responding to injury. This review discusses the metabolic reprogramming of immune cells, particularly macrophages, during ischemia-reperfusion injury and explores various therapeutic strategies that modulate these metabolic pathways to protect the heart during hypoxia. Understanding these interactions provides valuable insights and potential therapeutic targets for heart disease treatment.

Keywords: cardiac; cell interaction; hypoxia; metabolism; therapy.

Graphical abstract

Figure 1

Under Hypoxic Conditions, The Energy Metabolism of Cardiomyocytes Changes Many of the discussed pathways show protection against ischemia-reperfusion injury (IRI) (green arrows) or are protective if blocked (red arrows). This figure illustrates the roles of glycolysis, fatty acid metabolism, ketone body metabolism, and lactate metabolism.

Figure 2

Address Drugs and Treatment Measures Targeting Different Metabolic Pathways to Better Achieve Cardiac Protection Through Metabolic Pathway Intervention This figure illustrates the intricate network of metabolic pathways and regulatory factors involved in cellular energy homeostasis, particularly in cardiac metabolism. The diagram highlights the interactions between glucose and fatty acid metabolism under various physiological and pharmacological conditions. Hypoxia-inducible factor 1-alpha (HIF-1α) is activated under hypoxic conditions, leading to increased expression of glucose transporter 4 (GLUT4) and enhanced glucose uptake. HIF-1α also regulates pyruvate dehydrogenase kinase 4 (PDK4), which inhibits the pyruvate dehydrogenase complex, thereby reducing glucose oxidation and promoting glycolysis. The AMPK pathway intersects with HIF-1α, further enhancing glucose uptake and glycolysis. The phosphoinositide 3-kinase (PI3K) and AKT pathway is upregulated by AMPK, leading to increased glycolysis and energy provision. This pathway is essential for cellular survival and metabolism, especially under stress conditions. The peroxisome proliferator-activated receptors (PPARα, PPARβ, and PPARδ) are key regulators of fatty acid metabolism. They control fatty acid uptake, oxidation, and overall lipid homeostasis. The PGC-1α/PPARα pathway is particularly important in promoting fatty acid oxidation, thereby enhancing energy supply. βOHB = β-hydroxybutyrate; AcAc = acetyl-CoA; CAT-1 = carnitine acylcarnitine translocase; CD36 = cluster of differentiation 36; GSK3β, glycogen synthase kinase-3; HK-II = hexokinase II; HXHT = hypoxia-inducible transcription factor 1-α (HIF-1α) hydroxylase; IF1 = inhibitor of fatty acid oxidation; IPC = ischemic preconditioning; MCT = monocarboxylate transporter; SGLT2 = sodium–glucose co-transporter 2; VDAC1 = voltage-dependent anion channel 1.

Figure 3

Description of the Interaction Between Macrophages and Other Cells During Myocardial Hypoxia Hypoxia induces the release of reactive oxygen species (ROS) and MCP-1 from myocardial and endothelial cells, attracting monocytes that differentiate into macrophages. Oxidized low-density lipoprotein (ox-LDL) enters macrophages via the CD36 receptor, activating the nuclear factor (NF)-κB signaling pathway and triggering an inflammatory response. Hypoxia-inducible factor 1 (HIF-1) stabilizes and regulates the expression of various genes, including proinflammatory factors (such as tumor necrosis factor [TNF]-α and interleukin [IL]-1β) and PPARγ, further promoting CD36 expression and lipid metabolism. ROS activates the NF-κB pathway through Toll-like receptors (TLRs), leading to macrophages secreting transforming growth factor (TGF)-β and vascular endothelial growth factor (Vegf), which regulate endothelial cell function and promote myofibroblast formation. This process results in arterial wall necrosis and stress, ultimately causing myocardial cell damage and necrosis. MerTK = tyrosine kinase Mer; TIMD4+ = TMEM161B-mediated immune defense 4; Treg = T regulatory cell; other abbreviations as in Figure 2.

Central Illustration

Metabolic Pathways in Cardiac Myocytes During Hypoxia