Single-dose rosuvastatin ameliorates lung ischemia–reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage.

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Single-dose rosuvastatin ameliorates lung ischemia–reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension Satoshi Matsuo, MD, Yuriko Saiki, MD, PhD, Osamu Adachi, MD, PhD, Shunsuke Kawamoto, MD, PhD, Shinichi Fukushige, MD, PhD, Akira Horii, MD, PhD, Yoshikatsu Saiki, MD, PhD The Journal of Thoracic and Cardiovascular Surgery Volume 149, Issue 3, Pages 902-909 (March 2015) DOI: 10.1016/j.jtcvs.2014.10.030 Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Overview of the protocols. A, The normal group was administered saline, and the other groups were administered monocrotaline. In all treated groups, rats were sacrificed 22 hours after infusion of saline or rosuvastatin treatment. B, In the ischemia–reperfusion (IR) injury protocol, all treated groups (control + IR, statin + IR, and statin + mevalonolactone [mev] + IR), the left pulmonary artery was dissected and clamped 1 hour, followed by 4 hours of reperfusion, after which the rats were sacrificed. In the sham group, the left pulmonary artery was dissected, but not clamped, during the 5-hour period before the animals were sacrificed. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 902-909DOI: (10.1016/j.jtcvs.2014.10.030) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Effect of pulmonary hypertension (PH) on lung function, morphometry, histology, and endothelial function. After 21 days of monocrotaline treatment to establish the PH model, the effects of rosuvastatin and mevalonolactone (mev) were determined in terms of right ventricular systolic pressure, histology, arterial oxygen tension/inspired oxygen fraction (Pao2/Fio2) ratio, and wet/dry lung weight ratio. A, Monocrotaline significantly increased right ventricular systolic pressure compared with the normal group. B, Elastica-Masson staining in the normal group and control group. Original magnification, ×40. C and D, The Pao2/Fio2 ratio and wet/dry lung weight ratio were not influenced by rosuvastatin or mev. Error bars are mean ± standard error of the mean. E and F, Endothelial nitric oxide synthase (eNOS) expression was not altered by statin or mev administration. In contrast, phospho-eNOS expression was upregulated in the statin group compared with that in the control and statin + mev groups (P < .05). *P < .05; †P < .01. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 902-909DOI: (10.1016/j.jtcvs.2014.10.030) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Effect of ischemia–reperfusion (IR) on lung function, morphometry, and histology in the pulmonary hypertension (PH) rat model. After 21 days of monocrotaline treatment to establish PH, all animals (except sham) were subjected to IR injury and the above treatments. The groups were compared for histology, the arterial oxygen tension/inspired oxygen (Pao2/Fio2) ratio, and the wet/dry lung weight (W/D) ratio. A, The Pao2/Fio2 ratio was significantly higher in the statin + IR group than in the control + IR and statin + mevalonolactone (mev) + IR groups. Error bars are mean ± standard error of the mean. B, Statin treatment decreased the left lung W/D ratio to the level of the sham group. No significant difference in right lung W/D ratio was observed. Error bars are mean ± standard error of the mean. C, Hematoxylin and eosin staining showed that IR caused alveolar edema, which was suppressed by statins. Original magnification, ×40. *P < .05; †P < .01. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 902-909DOI: (10.1016/j.jtcvs.2014.10.030) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Effect of ischemia–reperfusion (IR) injury on endothelial nitric oxide synthase (eNOS) in the pulmonary hypertension rat model. After 21 days of monocrotaline treatment to establish PH, all animals (except sham) were subjected to IR and the above treatments. A, Although IR downregulated eNOS (control + IR and statin + mevalonolactone [mev] + IR), rosuvastatin (statin + IR) maintained eNOS expression at the level of the sham group (P < .01). B, Similar results were obtained for phospho-eNOS (P < .01). C, When the ratios of phospho-eNOS to total eNOS were calculated for comparison, the similar tendency was observed, but the difference between the groups was not statistically significant except for sham versus statin + mev + IR (P < .05). Error bars are mean ± standard error of the mean. D and E, Comparison of eNOS and phospho-eNOS levels between nonischemic and IR models. The eNOS levels were comparable only in the Statin group. Phospho-eNOS levels after IR were lower in all 3 groups compared with the nonischemic model; however, the phospho-eNOS level in the statin group was still maintained at a level equivalent to that of the nonischemic control. *P < .05; †P < .01. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 902-909DOI: (10.1016/j.jtcvs.2014.10.030) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Effect of ischemia–reperfusion (IR) injury on macrophage infiltration in a pulmonary hypertension rat model. After 21 days of monocrotaline treatment to establish pulmonary hypertension, all animals (except sham) were subjected to IR and the above treatments. A, Immunostaining of macrophages with CD68 antibody. Red arrows indicate CD68-positive cells. Original magnification, ×40. B, Macrophages (CD68-positive cells) were counted in 10 fields (×40, objective). Macrophage infiltration was significantly higher in the control group than in the sham group (P < .01). Rosuvastatin decreased macrophage infiltration in comparison with the control group (P < .01). Mev, Mevalonolactone. *P < .05, †P < .01. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 902-909DOI: (10.1016/j.jtcvs.2014.10.030) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions

Rosuvastatin preserved eNOS expression and inhibited macrophage infiltration after IR in PH lung. The Journal of Thoracic and Cardiovascular Surgery 2015 149, 902-909DOI: (10.1016/j.jtcvs.2014.10.030) Copyright © 2015 The American Association for Thoracic Surgery Terms and Conditions