Is there a causal link between intracellular Na elevation and metabolic remodelling in cardiac hypertrophy?

Abstract

Alterations in excitation-contraction coupling and elevated intracellular sodium (Na_i) are hallmarks of pathological cardiac remodelling that underline contractile dysfunction. In addition, changes in cardiac metabolism are observed in cardiac hypertrophy and heart failure (HF) that lead to a mismatch in ATP supply and demand, contributing to poor prognosis. A link between Na_i and altered metabolism has been proposed but is not well understood. Many mitochondrial enzymes are stimulated by mitochondrial calcium (Ca_mito) during contraction, thereby sustaining production of reducing equivalents to maintain ATP supply. This stimulation is thought to be perturbed when cytosolic Na_i is high due to increased Ca_mito efflux, potentially compromising ATP_mito production and leading to metabolic dysregulation. Increased Na_i has been previously shown to affect Ca_mito; however, whether Na_i elevation plays a causative role in energetic mismatching in the hypertrophied and failing heart remains unknown. In this review, we discuss the relationship between elevated Na_i, NaK ATPase dysregulation and the metabolic phenotype in the contexts of pathological hypertrophy and HF and their link to metabolic flexibility, capacity (reserve) and efficiency that are governed by intracellular ion homeostasis. The development of non-invasive analytical techniques using nuclear magnetic resonance able to probe metabolism in situ in the functioning heart will enable a better understanding of the underlying mechanisms of Na_i overload in cardiac pathophysiology. They will lead to novel insights that help to explain the metabolic contribution towards these diseases, the incomplete rescue observed with current therapies and a rationale for future energy-targeted therapies.

Keywords: bioenergetics; cardiac hypertrophy; metabolism; mitochondrial dysfunction; sodium.

Figure 1.. Major Na_i influx and efflux pathways and metabolic pathways involved in ATP supply.

The delivery of metabolic substrates, their selection and uptake are followed by OXPHOS. It involves electron shuttling from cytosolic to mitochondrial reducing equivalents, transfer of energy by electrons from reducing equivalents to ETC complexes and generation of electrochemical proton (H⁺) gradient within the mitochondrial intermembrane space (respiratory complexes I, II, II, III, IV). The release of H⁺ gradient is coupled to the synthesis of ATP from ADP + P_i by F₀,F₁-ATPase (complex V), contributing >95% of ATP synthesis under aerobic conditions. The final stage of myocardial ATP supply (phosphotransfer) involves delivery of ATP from mitochondria to sites of use. This involves ADP–ATP exchange across the inner mitochondrial membrane by the adenine nucleotide transporter (ANT) and propagation of local ATP/ADP disequilibria primarily by the creatine kinase (CK). Abbreviations: TAG, triacylglycerol; PCr, phosphocreatine; ANT, adenine nucleotide transporter; GLUT, glucose transporter; CD36, fatty acid transporter; PPP, pentose phosphate pathway; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; CPT, carnitine palmitoyltransferase; CACT, carnitine–acylcarnitine translocase; MCU, mitochondrial calcium uniporter; α-KDH, α-ketoglutarate dehydrogenase; IDH, isocitrate dehydrogenase; mitoCK, mitochondrial creatine kinase; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; Q, quinone pool; c, cytochrome c; MPC, mitochondrial pyruvate carrier; e⁻, electrons; CGP, mitochondrial Na–Ca exchanger inhibitor CGP-37157. *Mitochondrial calcium-sensitive dehydrogenases (pyruvate dehydrogenase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase).

Figure 2.. Schematic depiction of a structure–function relationship (regulation) between PLM and Na pump.

The cytoplasmic tail of unphosphorylated PLM interacts closely with the membrane and α-subunit of Na pump, whereas phosphorylation alters the association between the pump and PLM by moving the cytosolic arm away from the pump, but not by promoting their dissociation. Phosphorylation or ablation of PLM relieves inhibition of the Na pump by increasing its V_max and apparent Na affinity. Under stress, phosphorylation of PLM allows the heart to reduce its Na and Ca load and prevents lethal arrhythmias. Adapted from Pavlovic et al. [15].

Figure 3.. Representative ³¹P NMR spectra, triple-quantum-filtered ²³Na and conventional 1D ²³Na NMR spectra from perfused control and hypertrophied mouse hearts.

The spectra displayed in the left panel (a, c and e) are from a control heart, while those displayed in the right panel (b, d and f) are from a hypertrophied heart. All NMR data were acquired as previously described [51] using a Bruker Avance III 400 MHz wide-bore spectrometer. Briefly, a and b show ³¹P spectra, c and d show triple-quantum-filtered (TQF) ²³Na NMR spectra, while e and f show conventional single-quantum ²³Na NMR spectra acquired at the end of the perfusion during infusion of 5 mM Tm(DOTP).