Divergent cardiopulmonary actions of heme oxygenase enzymatic products in chronic hypoxia.
BACKGROUND
Hypoxia and pressure-overload induce heme oxygenase-1 (HO-1) in cardiomyocytes and vascular smooth muscle cells (VSMCs). HO-1(-/-) mice exposed to chronic hypoxia develop pulmonary arterial hypertension (PAH) with exaggerated right ventricular (RV) injury consisting of dilation, fibrosis, and mural thrombi. Our objective was to identify the HO-1 product(s) mediating RV protection from hypoxic injury in HO-1(-/-) mice.


RESULTS
HO-1(-/-) mice were exposed to seven weeks of hypoxia and treated with inhaled CO or biliverdin injections. CO reduced right ventricular systolic pressure (RVSP) and prevented hypoxic pulmonary arteriolar remodeling in both HO-1(-/-) and control mice. Biliverdin had no significant effect on arteriolar remodeling or RVSP in either genotype. Despite this, biliverdin prevented RV failure in the hypoxic HO-1(-/-) mice (0/14 manifested RV wall fibrosis or thrombus), while CO-treated HO-1(-/-) mice developed RV insults similar to untreated controls. In vitro, CO inhibited hypoxic VSMC proliferation and migration but did not prevent cardiomyocyte death from anoxia-reoxygenation (A-R). In contrast, bilirubin limited A-R-induced cardiomyocyte death but did not inhibit VSMC proliferation and migration.


CONCLUSIONS
CO and bilirubin have distinct protective actions in the heart and pulmonary vasculature during chronic hypoxia. Moreover, reducing pulmonary vascular resistance may not prevent RV injury in hypoxia-induced PAH; supporting RV adaptation to hypoxia and preventing RV failure must be a therapeutic goal.
Vitali
Sally H
SH
Division of Critical Care Medicine, Children's Hospital Boston, Boston, Massachusetts, United States of America.
Mitsialis
S Alex
SA
Liang
Olin D
OD
Liu
Xiaoli
X
Fernandez-Gonzalez
Angeles
A
Christou
Helen
H
Wu
Xinqi
X
McGowan
Francis X
FX
Kourembanas
Stella
S
D000818:Animals; D017209:Apoptosis; D001663:Bilirubin / Q000494:pharmacology; D016923:Cell Death; D002465:Cell Movement; D049109:Cell Proliferation; D005838:Genotype; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism*; D000860:Hypoxia; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D051381:Rats
D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin