Affiliation:
1. Department of Medicine Queen’s University Kingston Ontario Canada
2. Queen’s CardioPulmonary Unit Queen’s University Kingston Ontario Canada
3. Department of Biomedical and Molecular Sciences Queen’s University Kingston Ontario Canada
4. Department of Cellular and Molecular Medicine University of Ottawa Ottawa Ontario Canada
5. Children’s Hospital of Eastern Ontario Research Institute Ottawa Ontario Canada
6. Sinclair Centre for Regenerative Medicine Ottawa Hospital Research Institute Ottawa Ontario Canada
7. Department of Medicine The University of Chicago Chicago IL USA
Abstract
Background
As partial pressure of oxygen (pO
2
) rises with the first breath, the ductus arteriosus (DA) constricts, diverting blood flow to the pulmonary circulation. The DA's O
2
sensor resides within smooth muscle cells. The DA smooth muscle cells’ mitochondrial electron transport chain (ETC) produces reactive oxygen species (ROS) in proportion to oxygen tension, causing vasoconstriction by regulating redox‐sensitive ion channels and enzymes. To identify which ETC complex contributes most to DA O
2
sensing and determine whether ROS mediate O
2
sensing independent of metabolism, we used electron leak suppressors, S1QEL (suppressor of site I
Q
electron leak) and S3QEL (suppressor of site III
Qo
electron leak), which decrease ROS production by inhibiting electron leak from quinone sites I
Q
and III
Qo
, respectively.
Methods and Results
The effects of S1QEL, S3QEL, and ETC inhibitors (rotenone and antimycin A) on DA tone, mitochondrial metabolism, O
2
‐induced changes in intracellular calcium, and ROS were studied in rabbit DA rings, and human and rabbit DA smooth muscle cells. S1QEL's effects on DA patency were assessed in rabbit kits, using micro computed tomography. In DA rings, S1QEL, but not S3QEL, reversed O
2
‐induced constriction (
P
=0.0034) without reducing phenylephrine‐induced constriction. S1QEL did not inhibit mitochondrial metabolism or ETC‐I activity. In human DA smooth muscle cells, S1QEL and rotenone inhibited O
2
‐induced increases in intracellular calcium (
P
=0.02 and 0.001, respectively), a surrogate for DA constriction. S1QEL inhibited O
2
‐induced ROS generation (
P
=0.02). In vivo, S1QEL prevented O
2
‐induced DA closure (
P
<0.0001).
Conclusions
S1QEL, but not S3QEL, inhibited O
2
‐induced rises in ROS and DA constriction ex vivo and in vivo. DA O
2
sensing relies on pO
2
‐dependent changes in electron leak at site I
Q
in ETC‐I, independent of metabolism. S1QEL offers a therapeutic means to maintain DA patency.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
2 articles.
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