Energetic Metabolic Roles in Pulmonary Arterial Hypertension and Right Ventricular Remodeling

The survival of patients with pulmonary arterial hypertension is closely related with right ventricular function. During the progression of right ventricular remodeling, energetic metabolism shifts from oxidative mitochondrial metabolism to glycolysis. In normal physiological conditions, cardiomyocytes use major sources of glucose and fatty acids to sustain a continuous systolic workload and energy supply. This allows the heart to choose the most efficient substrate to response to environmental stimuli. Therefore, ATP production of glucose is the preferred energy source than fatty acids in right ventricular remodeling. However, the metabolic fate of glucose altered because mitochondrial metabolism is actively suppressed. Metabolic shift towards aerobic glycolysis and down-regulation of mitochondrial oxidation, is called the Warburg effect. Studies on animal models and human RVF suggest that there is reduced glucose oxidation and increased glycolysis in both adaptive and maladaptive right ventricular failure. Accordingly, a gate-keeping enzyme, pyruvate dehydrogenase kinase (PDK) is activated and inhibited pyruvate into the mitochondria with increased lactate dehydrogenase. Therefore, augmentation of glucose oxidation is beneficial in right ventricular remodeling and can be achieved by inhibition of PDK and fatty acid oxidation. As a PDK inhibitor, Dicholoracetate (DCA) can reduce pyruvate dehydrogenase phosphorylation and partially restore RV structure and function by promoting glucose and mitochondrial oxidation. Moreover, the partial inhibitors of fatty acid oxidation would be offered the utilization to improve right ventricular function. Although metabolic targeting drugs can be beneficial to right ventricular remodeling, the advantage of modulating metabolic shift into an enhanced clinical performance still remains to be determined. Keywords: Pulmonary arterial hypertension, right ventricular remodeling, mitochondrial metabolism, metabolic shift, glycolysis.