Heparin Reduces Overcirculation-Induced Pulmonary Artery Remodeling Through P38 MAPK in Piglet Gaofeng Zhao, MD, PhD, Jingjing Seng, MD, PhD, John Beagle,

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Heparin Reduces Overcirculation-Induced Pulmonary Artery Remodeling Through P38 MAPK in Piglet Gaofeng Zhao, MD, PhD, Jingjing Seng, MD, PhD, John Beagle, BS, Olga Syrkina, MD, Charles A. Hales, MD The Annals of Thoracic Surgery Volume 99, Issue 5, Pages 1677-1684 (May 2015) DOI: 10.1016/j.athoracsur.2014.12.061 Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 The left lower lobe pulmonary artery (LLLPA) to thoracic aortic artery (TAA) shunt setup and how to calculate the wall thickness percentage (WT%). (A) The LLLPA was connected to TAA by end-to-side anastomosis. (B) The approach used to calculate the vascular WT%. (LLL = left lower lobe; LUL = left upper lobe.) The Annals of Thoracic Surgery 2015 99, 1677-1684DOI: (10.1016/j.athoracsur.2014.12.061) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Effects of left lower lobe pulmonary artery (LLLPA) to thoracic aortic artery (TAA) shunt on the LLL. (A) Shunt caused significant LLLPA remodeling, which features remarkable medial hyperplasia (Elastin Van Gieson staining). (*p > 0.05; **p < 0.001; 5 piglets in each group. (w = week; WT% = wall thickness percentage.) (B) Shunt significantly increased the LLLPA flow immediately after shunt setup (* versus ** p < 0.005; 5 piglets in each group), but gradually decreased over the next 4 weeks (** versus *** p < 0.01; * versus *** p > 0.05; 5 piglets in each group). (C) Sham-treated piglets showed no evident changes in the LLLPpa 20 minutes after the shunt setup or 4 weeks later (*p > 0.05; 5 piglets in each group). (D) Shunt induced remarkable LLLPA pressure (LLLPpa) increase 20 minutes after the shunt setup (* versus ** p < 0.01; 5 piglets in each group); 4 weeks later, a more significant LLLPpa increase was caused by the chronic LLLPA-to-TAA shunt (* versus ** versus *** p < 0.01; 5 piglets in each group ). Shunt did not cause LLL PVR increase immediately after setup, but resulted in significant lower left lobe pulmonary vascular resistance (LLL PVR) increase over 4 weeks of observation (*p > 0.05; * versus ** p < 0.001; 5 piglets in each group). (Open bars = baseline; striped bars = 20 minutes after sham/shunt; checked bars = 4 weeks after sham/shunt.) The Annals of Thoracic Surgery 2015 99, 1677-1684DOI: (10.1016/j.athoracsur.2014.12.061) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Effects of heparin treatment on the shunted lobes. (A–D) Elastin Van Gieson staining of the left lower lobe pulmonary artery (LLLPA) in different groups. (w = weeks.) (E) Four weeks of heparin treatment limited the peribronchial arteriole wall thickness (WT%) significantly (*p > 0.05; **p > 0.05; ***p < 0.005; 5 piglets in each group). (F) Heparin treatment reduced the LLPA pressure (LLLPpa) increase (*p > 0.05; **p > 0.05; ***p < 0.005; 5 piglets in each group). (G) Chronic shunt led to significantly increased lower left lobe pulmonary vascular resistance (LLL PVR), and heparin treatment limited the shunt-induced LLL PVR increase (*p > 0.05; **p > 0.05; * versus ** p < 0.01; 5 piglets in each group). (H) Chronic shunt resulted in increased LLLPA flow (*p > 0.05; **p > 0.05; * versus ** p < 0.05; 5 piglets in each group), but heparin treatment on the shunted piglets limited the gradual flow decrease from that immediately after shunt setup (** versus *** p < 0.01; * versus *** p < 0.005; 5 piglets in each group). The Annals of Thoracic Surgery 2015 99, 1677-1684DOI: (10.1016/j.athoracsur.2014.12.061) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Effects of shunt and heparin on mean systemic blood pressure (msBP), heart rate (HR), cardiac output (CO), cardiac index (CI), arterial component of pulmonary vascular resistance (PVRa), and weight ratio of right ventricle to left ventricle plus ventricular septum (RV/LVS). The localized shunt between left lower lobe pulmonary artery (LLLPA) and thoracic aortic artery (TAA) and heparin therapy did not affect the (A) msBP, (B) heart rate, (C) cardiac output, (D) cardiac index, (E) PVRa, or (F) RV/LVS (F) in groups (one-way analysis of variance p > 0.05; 5 piglets in each group). The Annals of Thoracic Surgery 2015 99, 1677-1684DOI: (10.1016/j.athoracsur.2014.12.061) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 5 Effects of shunt and heparin on arterial oxygen saturation (SaO2%), hematocrit (Hct%), pH, weight gain (WG), mean pulmonary artery pressure (mPAP), and mean pulmonary wedge pressure (mPWP). The localized shunt setup and heparin therapy did not affect the (A) SaO2%, (B) Hct%, (C) pH, (D) WG, (E) mPAP, or (F) mPWP in groups (one-way analysis of variance p > 0.05; 5 piglets in each group). The Annals of Thoracic Surgery 2015 99, 1677-1684DOI: (10.1016/j.athoracsur.2014.12.061) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 6 Expression of P38 mitogen-activated protein kinases (MAPK) expression is increased by shunt and decreased by heparin treatment. (A) Shunted left lower lobes presented much higher P38 MAPK expression but did not show any changes in the expressions of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), P27, beta fibroblast growth factor (beta-FGF), proliferating cell nuclear antigen (PCNA), or Ki67. (B) Heparin significantly decreased P38 MAPK expression in the shunted lung lobes (* versus ** p < 0.01; 5 piglets in each group). (GAPDH = glyceraldehyde-3-phosphate dehydrogenase.) The Annals of Thoracic Surgery 2015 99, 1677-1684DOI: (10.1016/j.athoracsur.2014.12.061) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions

Fig 7 Effects of heparin on the growth of cultured pulmonary vascular smooth muscle cells (SMC) and P38 mitogen-activated protein kinases (MAPK) expression. (A) Heparin had significant inhibitory effects on VSMC growth; P38 MAPK inhibitor also showed reductive effect on the growth; combined treatment of heparin and inhibitor did not have additive suppression on VSMC growth (a versus b, c, and d: p < 0.01; b versus c versus d: p > 0.05). (Diamonds = fetal calf serum [FCS]; triangles = FCS/P38 inhibitor; squares = FCS/heparin; crosses = FCS/heparin/P38 inhibitor.) (B) Heparin significantly reduced FCS-stimulated P38 MAPK expression in the cultured VSMC (* versus ** p < 0.01; 5 piglets in each group). (GAPDH = glyceraldehyde-3-phosphate dehydrogenase.) The Annals of Thoracic Surgery 2015 99, 1677-1684DOI: (10.1016/j.athoracsur.2014.12.061) Copyright © 2015 The Society of Thoracic Surgeons Terms and Conditions