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* From the Children’s Hospital Boston, Boston, MA.
Correspondence to: Sally H. Vitali, MD, MSICU Office, FA517, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115; e-mail: sally.vitali{at}tch.harvard.edu
Heme oxygenase (HO)-1 null mice have a maladaptive right ventricular (RV) response to chronic hypoxia-induced pulmonary hypertension. After 7 weeks of exposure to 8 to 10% fraction of inspired oxygen, the majority of HO-1 null mice develop evidence of RV oxidative stress, apoptosis, and infarction, while wild-type mice do not. The cytoprotective effects of HO-1 are thought to result from its enzymatic products carbon monoxide (CO), a vasodilator with antiinflammatory effects, and bilirubin, an antioxidant.
In order to determine whether inhaled CO or injected biliverdin (converted to bilirubin by biliverdin reductase) protects the HO-1 null mouse from RV infarction during exposure to chronic hypoxia, 10-week-old mice were exposed to 9% fraction of inspired oxygen for 7.5 weeks in two chambers. In chamber A, 30 mice (15 HO-1 null mice and 15 wild-type mice) inhaled 20 ppm CO throughout the hypoxic exposure. In chamber B, 30 mice (14 HO-1 null mice and 16 wild-type mice) were treated with daily intraperitoneal injections of 50 µmol/kg biliverdin HCl, and 30 mice (15 HO-1 null mice and 15 wild-type mice) served as hypoxic controls. Half of these hypoxic controls also received daily injections of phosphate-buffered saline solution (biliverdin vehicle). Nineteen mice were normoxic controls; 10 mice, distributed among all groups, died during the experiment. At the end of the experiment, mice were anesthetized, and the heart was perfused with cold phosphate-buffered saline solution and removed. Biventricular (BV) weights were determined and normalized to animal weight (BV index). The heart was preserved and embedded for sectioning and staining.
Hypoxic mice had a higher BV index compared with normoxic mice (mean BV index, 0.0059 vs 0.0040, respectively; p < 0.01). HO-1 null mice responded to chronic hypoxia with a significantly higher BV index compared with hypoxic wild-type mice (0.0068 vs 0.0059, respectively; p < 0.05), but HO-1 null mice treated with biliverdin were protected from this increase (untreated mice, 0.0068; biliverdin-treated mice, 0.0059; p < 0.01). CO treatment had no effect on the BV index of HO-1 null mice or wild-type mice. Masson trichrome staining showed that while none of the wild-type mice developed fibrosis of the RV wall, 5 of 11 HO-1 null mice that had been exposed to hypoxia alone and 9 of 14 HO-1 null mice that were exposed to hypoxia plus CO developed wall fibrosis. In contrast, none of the biliverdin-treated HO-1 null mice developed fibrosis. In all mice exposed to hypoxia, regardless of genotype, inhaled CO reduced pulmonary arteriolar vascular wall thickness to levels similar to normoxic animals (mean percentage wall thickness: hypoxia, 28%; hypoxia + CO, 24%; normoxia, 22%; p < 0.05 [for hypoxia group vs other groups]). In contrast, biliverdin treatment had no effect on pulmonary arteriolar wall thickness.
These results provide evidence that daily treatment with the antioxidant biliverdin prevents the maladaptive RV response to chronic hypoxia seen in HO-1 null mice, but treatment with inhaled CO at 20 ppm does not prevent this response. Conversely, treatment with inhaled CO lessens the pulmonary vascular remodeling from hypoxia but injected biliverdin does not.
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