Hypoxia-induced glucose-6-phosphate dehydrogenase overexpression and -activation in pulmonary artery smooth muscle cells: implication in pulmonary hypertension

Abstract

Severe pulmonary hypertension is a debilitating disease with an alarmingly low 5-yr life expectancy. Hypoxia, one of the causes of pulmonary hypertension, elicits constriction and remodeling of the pulmonary arteries. We now know that pulmonary arterial remodeling is a consequence of hyperplasia and hypertrophy of pulmonary artery smooth muscle (PASM), endothelial, myofibroblast, and stem cells. However, our knowledge about the mechanisms that cause these cells to proliferate and hypertrophy in response to hypoxic stimuli is still incomplete, and, hence, the treatment for severe pulmonary arterial hypertension is inadequate. Here we demonstrate that the activity and expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, are increased in hypoxic PASM cells and in lungs of chronic hypoxic rats. G6PD overexpression and -activation is stimulated by H2O2. Increased G6PD activity contributes to PASM cell proliferation by increasing Sp1 and hypoxia-inducible factor 1α (HIF-1α), which directs the cells to synthesize less contractile (myocardin and SM22α) and more proliferative (cyclin A and phospho-histone H3) proteins. G6PD inhibition with dehydroepiandrosterone increased myocardin expression in remodeled pulmonary arteries of moderate and severe pulmonary hypertensive rats. These observations suggest that altered glucose metabolism and G6PD overactivation play a key role in switching the PASM cells from the contractile to synthetic phenotype by increasing Sp1 and HIF-1α, which suppresses myocardin, a key cofactor that maintains smooth muscle cell in contractile state, and increasing hypoxia-induced PASM cell growth, and hence contribute to pulmonary arterial remodeling and pathogenesis of pulmonary hypertension.

Lung Circulation

“…PASMCs from Fawn-hooded (18), chronically hypoxic and Su/Hx rats (105) and PAH patients (704) exhibit a phenotypic switch such that instead of mitochondrial metabolism, these cells preferentially use aerobic glycolysis. This type of bioenergetic shift confers a survival/growth advantage since glucose/glycolytic intermediates are substrates utilized by the pentose phosphate shunt to generate reduced nicotinamide adenine dinucleotide phosphate and nucleotides.…”

“…This type of bioenergetic shift confers a survival/growth advantage since glucose/glycolytic intermediates are substrates utilized by the pentose phosphate shunt to generate reduced nicotinamide adenine dinucleotide phosphate and nucleotides. The mechanisms underlying the switch to aerobic glycolysis may be related to overactivation of glucose-6-phosphate dehydrogenase (105) and HIF-dependent upregulation of glycolytic (710) and proproliferative (105,106) genes. Additionally, hypoxia-induced upregulation of glucose-6-phosphate dehydrogenase activity was correlated with reduced expression of contractile proteins in PASMCs (106), suggesting that metabolic derangements may underlie the phenotypic switch from a "contractile" to "synthetic" SMC phenotype.…”

“…Animal studies using dehydroepiandrosterone, a steroid hormone that, among other actions, opens K + channels (71) or dichloroacetate, a metabolic modulator that also increases the expression of K + channels (412,419), showed promising outcomes in CH and MCT-treated animals. In the Su/Hx model, dehydroepiandrosterone attenuated PH and preserved RV contractile function via reduced RV oxidative stress, capillary rarefaction, apoptosis, autophagy and fibrosis (14,105,521). While it is unclear whether the beneficial effects of either drug were specifically due to actions on K + channels, the use of dichloroacetate to treat PAH is currently in Phase 1 clinical trials in Canada and a small pilot study found dehydroepiandrosterone reduced mean P PA and PVR and improved 6-min walk distances in COPD patients with PH (148).…”

The role of glucose-6-phosphate dehydrogenase in adipose tissue inflammation in obesity

“…[46][47][48] Because adipose tissue simultaneously faces those signaling pathways in obesity, further studies are needed to precisely delineate the signaling pathways leading to upregulation of G6PD in obesity. In addition, another open question is what molecular events are responsible for dual, opposing effects of G6PD deficiency on ROS balance in different cell types.…”

20-HETE-induced mitochondrial superoxide production and inflammatory phenotype in vascular smooth muscle is prevented by glucose-6-phosphate dehydrogenase inhibition

“…G6PD inhibition relaxes pulmonary arteries by decreasing intracellular calcium (20), prevents switching of vascular smooth muscle cells to a synthetic phenotype (9,10), and reduces pulmonary hypertension (9,47). However, whether prolonged hypoxia-induced 20-HETE-synthesis is G6PD dependent or independent and whether G6PD modulates 20-HETE signaling in the vascular smooth muscle remain unknown.…”