title: Potential role of mitochondrial superoxide decreasing ferrochelatase and heme in coronary artery soluble guanylate cyclase depletion by angiotensin II.
abstract: Oxidation of the soluble guanylate cyclase (sGC) heme promotes loss of regulation by nitric oxide (NO) and depletion of sGC. We hypothesized that angiotensin II (ANG II) stimulation of mitochondrial superoxide by its type 1 receptor could function as a potential inhibitor of heme biosynthesis by ferrochelatase, and this could decrease vascular responsiveness to NO by depleting sGC. These processes were investigated in a 24-h organoid culture model of bovine coronary arteries (BCA) with 0.1 μM ANG II. Treatment of BCA with ANG II increased mitochondrial superoxide, depleted mitochondrial superoxide dismutase (SOD2), ferrochelatase, and cytochrome oxidase subunit 4, and sGC, associated with impairment of relaxation to NO. These processes were attenuated by organoid culture with 8-bromo-cGMP and/or δ-aminolevulinic acid (a stimulator of sGC by protoporphyrin IX generation and heme biosynthesis). Organoid culture with Mito-TEMPOL, a scavenger of mitochondrial matrix superoxide, also attenuated ANG II-elicited ferrochelatase depletion and loss of relaxation to NO, whereas organoid culture with Tempol, an extramitochondrial scavenger of superoxide, attenuated the loss of relaxation to NO by ANG II, but not ferrochelatase depletion, suggesting cytosolic superoxide could be an initiating factor in the loss of sGC regulation by NO. The depletion of cytochrome oxidase subunit 4 and sGC (but not catalase) suggests that sGC expression may be very sensitive to depletion of heme caused by ANG II disrupting ferrochelatase activity by increasing mitochondrial superoxide. In addition, cGMP-dependent activation of protein kinase G appears to attenuate these ANG II-stimulated processes through both preventing SOD2 depletion and increases in mitochondrial and extramitochondrial superoxide.
authors.affiliation: Department of Physiology, Translational Center for Pulmonary Hypertension, New York Medical College, Valhalla, New York and.
authors.forename: Dhara
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Physiology, Translational Center for Pulmonary Hypertension, New York Medical College, Valhalla, New York and.
authors.forename: Raed
authors.initials: R
authors.lastname: Alhawaj
authors.affiliation: Department of Physiology, Translational Center for Pulmonary Hypertension, New York Medical College, Valhalla, New York and.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Kelly
authors.affiliation: Department of Physiology, Translational Center for Pulmonary Hypertension, New York Medical College, Valhalla, New York and.
authors.forename: John J O
authors.initials: JJ
authors.lastname: Accarino
authors.affiliation: Department of Pharmacology, Translational Center for Pulmonary Hypertension, New York Medical College, Valhalla, New York.
authors.forename: Anand
authors.initials: A
authors.lastname: Lakhkar
authors.affiliation: Department of Pharmacology, Translational Center for Pulmonary Hypertension, New York Medical College, Valhalla, New York.
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Gupte
authors.affiliation: Department of Physiology, Translational Center for Pulmonary Hypertension, New York Medical College, Valhalla, New York and.
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Physiology, Translational Center for Pulmonary Hypertension, New York Medical College, Valhalla, New York and mike_wolin@nymc.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D003576:Electron Transport Complex IV / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology; D005294:Ferrochelatase / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006418:Heme / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology; D009940:Organoids; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
chemical_list: D000804:Angiotensin II; D017869:Cyclic GMP-Dependent Protein Kinases; D003576:Electron Transport Complex IV; D020536:Enzyme Activators; D005294:Ferrochelatase; D016166:Free Radical Scavengers; D006418:Heme; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D000071756:Soluble Guanylyl Cyclase; D013482:Superoxide Dismutase; D013481:Superoxides; D014665:Vasodilator Agents; D000099156:Superoxide Dismutase 2
keywords: guanosine 3′,5′-cyclic monophosphate; protoporphyrin IX, nitric oxide; δ-aminolevulinic acid