Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

Abstract

Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.

Metabolic Reprogramming Regulates the Proliferative and Inflammatory Phenotype of Adventitial Fibroblasts in Pulmonary Hypertension Through the Transcriptional Corepressor C-Terminal Binding Protein-1

“…2B). These findings are consistent with our recent observations of oxygen-independent increased mitochondrial and cytoplasmic (NOX4 generated) ROS production in both human and bovine PH-Fibs 25 .…”

Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension

“…Further strengthening this association are Wnt variants present in multiple patients. Finally, to strengthen the gene variant findings, we tested the hypothesis that this pathway was of relevance to the IPAH (37,38). Using human lung fibroblast lines, we found evidence of altered expression of Wnt pathway-modulating genes; borderline increased expression of Wisp1, a Wnt target regulating proliferation; and significantly increased Wnt activity in response to stimulation by LiCl.…”

“…Fibroblasts have previously been shown to be important in PAH, are from a tissue of relevance in PAH, and can be isolated from patients with IPAH (37,38). We first tested the hypothesis that GVs in Wnt genes may result in altered expression of Wnt genes.…”

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…The Pasteur Effect is observed in normal oxygen levels, which results in the activation of oxidative phosphorylation and the inhibition of glycolysis. However, cancer cells develop a hypoxia-induced scape mechanism, which switches oxidative phosphorylation to glycolysis (also known as the Warburg effect) to support high proliferation [23, 24]. In order to target tumor cells with this profile, new therapeutic strategies that act on glycolytic pathway are being developed.…”