Redox regulation of responses to hypoxia and NO-cGMP signaling in pulmonary vascular pathophysiology.
Pulmonary vascular responses elicited by hypoxia and NO-cGMP signaling are potentially influenced by ROS and redox mechanisms that change during the progression of disease processes. Our studies in endothelium-rubbed bovine pulmonary arteries suggest increased glucose-6-phosphate dehydrogenase levels (compared to coronary arteries) seem to maintain a tonic peroxide-mediated relaxation removed by hypoxia through NADPH fueling superoxide generation from Nox oxidase. The activities of glucose-6-phosphate dehydrogenase, oxidases (i.e., Nox4), and systems metabolizing superoxide and peroxide markedly influence hypoxic pulmonary vasoconstriction (HPV). Activation of soluble guanylate cyclase and cGMP protein kinase seems to participate in peroxide-elicited relaxation. Endogenous NO helps maintain low pulmonary arterial pressure and suppresses HPV. Multiple redox processes potentially occurring during the progression of pulmonary hypertension may also attenuate NO-mediated relaxation beyond its scavenging by superoxide, including oxidation of guanylate cyclase heme and thiols normally maintained by cytosolic NADPH redox control.
Wolin
Michael S
MS
Department of Physiology and Pulmonary Hypertension Center, New York Medical College, Valhalla, New York, USA. mike_wolin@nymc.edu
Gupte
Sachin A
SA
Mingone
Christopher J
CJ
Neo
Boon Hwa
BH
Gao
Qun
Q
Ahmad
Mansoor
M
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D011651:Pulmonary Artery / Q000378:metabolism* / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*
D009569:Nitric Oxide; D006152:Cyclic GMP