Volume 11 Supplement 1

5th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access

Redox regulation of responses to hypoxia and NO-cGMP signaling in pulmonary vascular pathophysiology

  • Michael S Wolin1Email author,
  • Boon Hwa Neo1,
  • Dhara Patel1,
  • Raed Alhawaj1,
  • Sharath Kandhi1 and
  • Mansoor Ahmad1
BMC Pharmacology201111(Suppl 1):O8

https://doi.org/10.1186/1471-2210-11-S1-O8

Published: 1 August 2011

There is much controversy in mechanisms controlling the pulmonary arterial response to acute and chronic hypoxia. Our previous work suggests bovine pulmonary arteries (BPA) contract to hypoxia via removal of a relaxation mediated by hydrogen peroxide derived from superoxide generated by Nox4 [1]. In contrast, bovine coronary arteries (BCA) relax to hypoxia via cytosolic NADPH oxidation coordinating multiple processes that lower intracellular calcium [2]. Peroxide appears to relax BPA by both stimulation of soluble guanylate cyclase (sGC) and by a cGMP-independent activation of protein kinase G (PKG) resulting from thiol oxidation-mediated subunit dimerization [3]. A removal of both of these mechanisms appears to contribute to the hypoxic pulmonary vasoconstriction (HPV) response seen in BPA. In addition, PKG dimerization appears to participate in the relaxation of coronary arteries to hypoxia. BPA secrete superoxide derived from Nox2 into the extracellular environment, and increased extracellular SOD (ecSOD) activity appears to attenuate the HPV response by increasing extracellular peroxide levels from this extracellular source of superoxide. Increased peroxide generated by Nox2 or mitochondria also appears to attenuate the relaxation of BCA to hypoxia by stimulating ERK MAP kinase [4]. Exposure of mice to 21 days of hypoxia (10% O2) promotes pulmonary hypertension associated with decreased pulmonary artery and aortic contraction to phenylephrine, NO-mediated relaxation to acetylcholine (ACh) and responses to hypoxia. While increased pulmonary arterial expression of sGC has been reported in this mouse model of pulmonary hypertension, chronic hypoxia had minimal effects on relaxation to an NO donor. Catalase markedly restored contraction to phenylephrine and the aortic relaxation to hypoxia. Chronic treatment of mice with cobalt protoporphyrin IX, which induces heme oxygenase and ecSOD, attenuated the development of pulmonary hypertension without restoring relaxation to ACh. In addition, chronic treatment of mice with delta-aminolevulinic acid, a precursor to the sGC activator protoporphyrin IX and heme needed for sGC activation and heme oxygenase activity, also attenuated pulmonary hypertension development without restoring responses to ACh. Thus, redox mechanisms regulating PKG seem to be important contributors to vascular oxygen sensing mechanisms. In addition, increased ecSOD expression and PKG-mediated vasodilation to endogenously generated peroxide and other sGC activators may function as a protective mechanism against the development of hypoxia-induced pulmonary hypertension.

Declarations

Acknowledgements

These studies were supported by NIH Grants HL031069, HL043023, and HL066331.

Authors’ Affiliations

(1)
Department of Physiology, New York Medical College

References

  1. M Ahmad, MR Kelly, X Zhao, S Kandhi, MS Wolin: Roles for Nox4 in the contractile response of bovine pulmonary arteries to hypoxia. Am J Physiol Heart Circ Physiol. 2010, 298: H1879-1888. 10.1152/ajpheart.01228.2009.View ArticleGoogle Scholar
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  3. BN Neo, S Kandhi, MS Wolin: Roles for soluble guanylate cyclase and a thiol oxidation-elicited subunit dimerization of protein kinase G in pulmonary artery relaxation to hydrogen peroxide. Am J Physiol Heart Circ Physiol. 2010, 299: H1215-H1221.Google Scholar
  4. Q Gao, X Zhao, M Ahmad, MS Wolin: Mitochondrial-derived hydrogen peroxide inhibits relaxation of bovine coronary arterial smooth muscle to hypoxia through stimulation of ERK MAP kinase. Am J Physiol Heart Circ Physiol. 2009, 297: H2262-H2269. 10.1152/ajpheart.00817.2009.View ArticleGoogle Scholar

Copyright

© Wolin et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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