title: Glc-6-PD and PKG contribute to hypoxia-induced decrease in smooth muscle cell contractile phenotype proteins in pulmonary artery.
abstract: Persistent hypoxic pulmonary vasoconstriction (HPV) plays a significant role in the pathogenesis of pulmonary hypertension, which is an emerging clinical problem around the world. We recently showed that hypoxia-induced activation of glucose-6-phosphate dehydrogenase (Glc-6-PD) in pulmonary artery smooth muscle links metabolic changes within smooth muscle cells to HPV and that inhibition of Glc-6PD reduces acute HPV. Here, we demonstrate that exposing pulmonary arterial rings to hypoxia (20-30 Torr) for 12 h in vitro significantly (P < 0.05) reduces (by 30-50%) SM22α and smooth muscle myosin heavy chain expression and evokes HPV. Glc-6-PD activity was also elevated in hypoxic pulmonary arteries. Inhibition of Glc-6-PD activity prevented the hypoxia-induced reduction in SM22α expression and inhibited HPV by 80-90% (P < 0.05). Furthermore, Glc-6-PD and protein kinase G (PKG) formed a complex in pulmonary artery, and Glc-6-PD inhibition increased PKG-mediated phosphorylation of VASP (p-VASP). In turn, increasing PKG activity upregulated SM22α expression and attenuated HPV evoked by Glc-6-PD inhibition. Increasing passive tension (from 0.8 to 3.0 g) in hypoxic arteries for 12 h reduced Glc-6-PD, increased p-VASP and SM22α levels, and inhibited HPV. The present findings indicate that increases in Glc-6-PD activity influence PKG activity and smooth muscle cell phenotype proteins, all of which affect pulmonary artery contractility and remodeling.
authors.affiliation: Department of Biochemistry & Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
authors.forename: Sukrutha
authors.initials: S
authors.lastname: Chettimada
authors.forename: Dhwajbahadur K
authors.initials: DK
authors.lastname: Rawat
authors.forename: Nupur
authors.initials: N
authors.lastname: Dey
authors.forename: Robert
authors.initials: R
authors.lastname: Kobelja
authors.forename: Zachary
authors.initials: Z
authors.lastname: Simms
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Lincoln
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Gupte
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002417:Cattle; D015687:Cell Hypoxia / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000235:genetics; D011651:Pulmonary Artery / Q000378:metabolism / Q000502:physiology*; D014661:Vasoconstriction / Q000235:genetics / Q000502:physiology
chemical_list: D015415:Biomarkers; D008840:Microfilament Proteins; D009124:Muscle Proteins; C051615:transgelin; D005954:Glucosephosphate Dehydrogenase; D017869:Cyclic GMP-Dependent Protein Kinases; D018995:Myosin Heavy Chains