Metabolic dysfunction in pulmonary hypertension: the expanding relevance of the Warburg effect

Abstract

Background: Pulmonary hypertension (PH) is an enigmatic vascular syndrome characterized by increased pulmonary arterial pressure and adverse remodelling of the pulmonary arterioles and often of the right ventricle. Drawing parallels with tumourigenesis, recent endeavours have explored the relationship between metabolic dysregulation and PH pathogenesis.

Design: We will discuss the general mechanisms by which cellular stressors such as hypoxia and inflammation alter cellular metabolism. Based on those principles, we will explore the development of a corresponding metabolic pathophenotype in PH, with a focus on WHO Groups I and III, and the implications that these alterations may have for future treatment of this disease.

Results: Investigation of metabolic dysregulation in both the pulmonary vasculature and right ventricle during PH pathogenesis has provided a more unifying understanding of how disparate disease triggers coordinate end-stage disease manifestations. Namely, as defined originally in various cancers, the Warburg effect describes a chronic shift in energy production from mitochondrial oxidative phosphorylation to glycolysis. In many cases, this Warburg phenotype may serve as a central causative mechanism for PH progression, largely driving cellular hyperproliferation and resistance to apoptosis. Consequently, new therapeutic strategies have been increasingly pursued that target the Warburg phenotype. Finally, new technologies are increasingly becoming available to probe more completely the complexities of metabolic cellular reprogramming and may reveal distinct metabolic pathways beyond the Warburg effect that drive PH.

Conclusion: Studies of metabolic dysregulation in PH are just emerging but may offer powerful therapeutic means to prevent or even reverse disease progression at the molecular level.

Keywords: Glycolysis; Warburg effect; hypoxia; metabolism; mitochondria; pulmonary hypertension.

Figure 1

Vascular cell types in the pulmonary arteries undergo dramatic remodeling during PH, especially noted in PAH and hypoxia-induced PH. Up-regulation of growth factors, electrical remodeling, and persistent inflammation produce abnormal PASMCs that proliferate excessively, occluding the arteries and restricting blood flow. Metabolic and mitochondrial dysregulation are crucial to several of these processes, as mitochondrial hyperpolarization and the glycolytic shift lead to the up-regulation of stress factors and impaired release of apoptotic factors. Adapted with permission from .

Figure 2

Role of HIF and hypoxia in the Pasteur/Warburg effects. During hypoxic conditions, newly stabilized HIF up-regulates an array of glycolytic enzymes that activate anaerobic glycolysis and suppress the the electron transport chain (ETC) though inhibition of glucose oxidation and iron sulfur cluster assembly.

Figure 3

Electrical remodeling induced by metabolic reprogramming in diseased pulmonary vasculature. Down-regulation of voltage-gated potassium (K_v) channels prevents K⁺ efflux, leading to a high concentration of K⁺ in the cytosol. The resulting membrane depolarization triggers the opening of L-type calcium channels, which allows for Ca²⁺ influx. Calcium suppresses GSK-3, thus preventing inhibition of HK-II. HK-II then freely inhibits the voltage-dependent anion channel (VDAC) of the mitochondrial permeability transition pore (MPTP), causing mitochondrial hyperpolarization and preventing the release of pro-apoptotic factors through the MPTP. Ca²⁺ also promotes NFAT entry into the cell. NFAT further inhibits K_v channels, creating a feedback loop and augmenting the above responses.

Figure 4

End-diastolic (A) and end-systolic (B) cine short-axis images from a patient with PH. Hypertrophy and dilation of the right ventricle in PH is the result of the increased pressure placed on the ventricle to maintain blood flow in the face of high vascular resistance. Increased mass in the right ventricle leads to a higher oxygen requirement. Without the appropriate blood supply, this imbalance can lead to myocardial hypoxia and a variety of cellular abnormalities. Adapted with permission from .