Fatty Acid Metabolism in Pulmonary Arterial Hypertension: Role in Right Ventricular Dysfunction and Hypertrophy

Abstract

Pulmonary arterial hypertension (PAH) is a complex, multifactorial disease in which an increase in pulmonary vascular resistance leads to increased afterload on the right ventricle (RV), causing right heart failure and death. Our understanding of the pathophysiology of RV dysfunction in PAH is limited but is constantly improving. Increasing evidence suggests that in PAH RV dysfunction is associated with various components of metabolic syndrome, such as insulin resistance, hyperglycemia, and dyslipidemia. The relationship between RV dysfunction and fatty acid/glucose metabolites is multifaceted, and in PAH it is characterized by a shift in utilization of energy sources toward increased glucose utilization and reduced fatty acid consumption. RV dysfunction may be caused by maladaptive fatty acid metabolism resulting from an increase in fatty acid uptake by fatty acid transporter molecule CD36 and an imbalance between glucose and fatty acid oxidation in mitochondria. This leads to lipid accumulation in the form of triglycerides, diacylglycerol, and ceramides in the cytoplasm, hallmarks of lipotoxicity. Current interventions in animal models focus on improving RV dysfunction through altering fatty acid oxidation rates and limiting lipid accumulation, but more specific and effective therapies may be available in the coming years based on current research. In conclusion, a deeper understanding of the complex mechanisms of the metabolic remodeling of the RV will aid in the development of targeted treatments for RV failure in PAH.Keywords: pulmonary arterial hypertension, metabolic syndrome, fatty acid oxidation, glucose oxidation, right ventricle, fatty acid transporter (CD36), glucose transporters, insulin resistance, right ventricular lipotoxicity, lipotoxic cardiomyopathy. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by progressive obliteration of the pulmonary vasculature, right heart failure, and death. The pathobiology of PAH is complex, and presently there is no curative treatment. Although PAH is classically thought to be a disease of the lungs, the role played by right ventricular (RV) hypertrophy and dysfunction that ultimately results in right heart failure and death is understudied. RV failure is the most common cause of death in PAH, 1 yet there are no specific therapies aimed at improving RV adaptation or function. However, it is well documented that pathological RV remodeling in PAH can be reversed with lung transplantation or with pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension (CTEPH). 2-9 The molecular mechanisms that mediate the transition from adaptive RV compensation to failure or that can promote reversible RV remodeling are presently unknown. Recently, our group and others have found evidence indicating that intracellular lipid accumulation and decreased fatty acid oxidation (FAO) may be features of RV failure related to PAH. [10][11][12][13] This raises a question: In PAH, can accumulation of fatty acids promote RV dysfun...

Preventive aerobic training exerts a cardioprotective effect on rats treated with monocrotaline

“…). Soon physical training improved RV function without changing the PAH severity, which can be justified by some direct actions of the training in the RV, without decreasing the PAH, mechanisms have not been studied but have been elucidated in previous studies (Ryan & Archer ; Talati & Hemnes ). Other studies using this model evaluated cardiac function through catheterization (Colombo et al .…”

“…Another aspect to be considered is that the increase in physical activity has known effects on mitochondrial content, mitochondrial respiration and substrate utilization, which may very well have effects on the RV function of monocrotaline rats (treated or untreated) (Piao et al . ; Ryan & Archer ; Talati & Hemnes ). Further studies are necessary to investigate these molecular mechanisms.…”

“…; Mocumbi et al . ; Talati & Hemnes ). Data on the exact prevalence of PAH are unknown, and the true figure could be underestimated (Mocumbi et al .…”

Mitochondria in lung disease

“…Vascular obstruction occurs as a consequence of excessive proliferation and apoptosis resistance of vascular cells. Chronic repression of mitochondrial metabolism, including decreased mitochondrial FA oxidation and transport (24), is associated with metabolic switching from mitochondrial-derived glucose oxidation to cytoplasmic-derived anaerobic glycolysis (25). The metabolic shift to anaerobic glycolysis contributes mechanistically to the apoptosisresistant, proliferative phenotype of PH.…”

Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI–Cardiovascular Medical Research and Education Fund Workshop Report

“…Advancing knowledge about the molecular, cellular, and functional characteristics of the RV and pulmonary arteries will accelerate progress in the treatment of PH (38,39). It is a valid strategy to develop effective therapies that will be directed towards the RV, as the morbidity and mortality in PAH have been correlated best with hemodynamics and RV ejection fraction.…”