Mitochondrial and Metabolic Drivers of Pulmonary Vascular Endothelial Dysfunction in Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a deadly and increasingly prevalent vascular disease characterized by excessive pulmonary vascular remodeling and right ventricular dysfunction which leads to right heart failure, multiorgan dysfunction, and premature death. The cause of the vascular remodeling in PH remains elusive, and thus current treatments are marginally effective and prognosis of PH remains poor. Increasing evidence indicates the pathogenic importance of endothelial dysfunction in PH. However, the underlying mechanisms of such dysfunction are not well described. Endothelial apoptosis and hyperproliferation have been identified in patients with PH. Both are linked with the increased oxidative stress and inflammatory responses, and are influenced by various genetic and exogenous stresses. Importantly, contrary to historic dogma that suggested a negligible role for mitochondria and energy balance in endothelial pathology, recent findings have implicated the role of endothelial metabolism directly in PH. This chapter addresses the emerging role of mitochondria in pulmonary vascular endothelial dysfunction in PH. A more sophisticated understanding of the biochemical, metabolic, molecular, and physiologic underpinnings of this emerging paradigm should enable the development of a new generation of targeted therapies that will stunt or reverse pulmonary vascular remodeling.

Keywords: Endothelial cell; Metabolism; Mitochondria; Pulmonary hypertension.

Fig. 1

Relationships between metabolome, proteome, and genome in metabolic reprogramming of endothelial cells in PH. In typical cells under normal oxygen levels, a majority of pyruvate derived from glucose enters the mitochondria where it is oxidized in the TCA cycle to generate ATP to meet the cell’s energy demands. However, in PH endothelial cells, pyruvate is directed away from the mitochondria toward glycolysis in order to create lactate through the action of lactate dehydrogenase (LDH)—a process typically activated by low oxygen exposure. Lactate production in the presence of oxygen is termed “aerobic glycolysis” or the Warburg effect, a phenomenon common in cancer cells. In aerobic glycolysis, excess glucose is diverted through the pentose phosphate shunt (PPS) and serine/glycine biosynthesis pathway to create nucleotides. Fatty acids are critical for new membrane production and are synthesized from citrate in the cytosol by ATP-citrate lyase (ACL) to generate acetyl-CoA. Signals impacting levels of hypoxia inducible factor (HIF) and nuclear factor of activated T cells (NFAT) can increase expression of enzymes such as LDH to promote lactate production, as well as pyruvate dehydrogenase kinase to inhibit the action of pyruvate dehydrogenase and limit entry of pyruvate into TCA cycle. Highly proliferative endothelial cells need to produce excess lipid, nucleotide, and amino acids for the creation of new biomass. There is also increased use of glutamine as another fuel source, which enters the mitochondria and can be used to replenish TCA intermediates or to produce more pyruvate through the action of malic enzyme. Adapted with permission from Science [66]

Fig. 2

Pulmonary vascular stiffness controls major metabolites in anaplerosis and glycolysis in cultured pulmonary vascular cells and in PH-diseased primate and human samples. Glutaminase (GLS1) and pyruvate carboxylase (PC) generate the major anaplerotic metabolites (blue), feeding into the TCA cycle (black) and supporting the anabolic demand for biosynthesis (green). Lactate dehydrogenase A (LDHA) modulates glycolysis (red). As compared with soft ECM (left panel), ECM stiffening (stiff ECM, right panel) mechanoactivates the transcriptional co-activators YAP/TAZ to modulate metabolic enzymes including LDHA, GLS1, and PC—implicated in both glycolysis (LDHA) and anaplerosis (GLS1 and PC). As a result, lactate production increases, while intracellular glutamine declines accompanied by a robust increase of glutamate and aspartate, thus driving anaplerosis during accelerated glycolysis in endothelial dysfunction in PH. Adapted with permission from the Journal of Clinical Investigation [36]

Fig. 3

Potential therapeutic targets in PH based on mitochondrial and metabolic dysfunction of endothelial cells. This schematic of endothelial metabolic dysfunction in PH suggests several therapeutic targets (shown in red circles and listed on top of the figure) that have shown pre-clinical promise and in several cases are currently being tested in early-phase clinical trials. αKG α-ketoglutarate, ER endoplasmic reticulum, GLS glutaminase, HIF hypoxia-inducible factor, MCD malonyl-CoA decarboxylase, MnSOD manganese superoxide dismutase, MnTBAP Mn(III)tetrakis(4-benzoic acid)porphyrin chloride, mROS mitochondria-derived reactive oxygen species, NFAT nuclear factor of activated T cells, PDH pyruvate dehydrogenase, PDK pyruvate dehydrogenase kinase, TK tyrosine kinase. Adapted with permission from Circulation Research [67]