Pyruvate Kinase and Warburg Metabolism in Pulmonary Arterial Hypertension

Articles, see p 2451 and p 2468 Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy in which vascular cells proliferate too rapidly or are resistant to apoptosis. PAH is also characterized by increases in inflammation, vasoconstriction, and fibrosis. Ultimately, these vascular changes increase right ventricular afterload, leading to heart failure and death. Pulmonary vascular cells from patients with PAH have adaptations that ensure that their high rates of proliferation are not thwarted by energy limitations, mitochondria-mediated apoptosis, or inadequate rates of mitotic fission.1 Histological examination reveals the consequences of this proliferative diathesis, including intimal hyperplasia and plexiform lesions, medial hypertrophy, and adventitial fibrosis. The resulting endothelial dysfunction favors thrombosis and vasoconstriction; the hyperplasia of pulmonary artery smooth muscle cells (PASMCs) favors vasoconstriction; and the adventitial fibrosis results in stiff, noncompliant arteries. Two articles in this issue of Circulation describe a metabolic adaptation that is good for the abnormal cell but bad for the patient, namely a shift in glucose metabolism called the Warburg phenomenon. Otto Warburg, a German Nobel Laureate, described the predilection of cancer to support its rapid growth by a reliance on glycolysis despite an abundance of available oxygen. Warburg metabolism is a failure of 2 fundamental pathways: glucose metabolism and mitochondrial oxygen sensing. Glycolysis and glucose oxidation are normally coupled, meaning they occur in proportion to each other. The final products of glycolysis are ATP and pyruvate. Pyruvate enters the mitochondria via the mitochondrial pyruvate transporter and acts as the substrate for pyruvate dehydrogenase (PDH), which regulates glucose oxidation and supplies acetyl CoA to the Krebs cycle (Figure). Warburg metabolism represents a state of uncoupled glycolysis in that glycolysis is disproportionately elevated compared with mitochondrial pyruvate utilization and glucose oxidation. Warburg metabolism allows the cell a source of energy (glycolysis) while suppressing mitochondrial apoptosis and stimulating …