Title:Energetic Metabolic Roles in Pulmonary Arterial Hypertension and Right Ventricular Remodeling
Volume: 22
Issue: 31
Author(s): Rui Zhang and Zhi-Cheng Jing
Affiliation:
Keywords:
Pulmonary arterial hypertension, right ventricular remodeling, mitochondrial metabolism, metabolic shift, glycolysis.
Abstract: 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.
