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Capillary Degeneration and Right Ventricular Remodeling Due to Hypoxic Stress with Sugen5416

[ Vol. 15 , Issue. 6 ]

Author(s):

Eiki Woo, Ryuji Kato, Hideki Imano, Yuji Fujiwara, Yoshio Ijiri, Yoshikatsu Okada, Takehiro Yamaguchi, Yasukatsu Izumi, Minoru Yoshiyama, Takahiro Katsumata and Tetsuya Hayashi*   Pages 589 - 598 ( 10 )

Abstract:


Background: Sugen5416 (semaxinib) is an inhibitor of the vascular endothelial growth factor (VEGF) receptor. A rat model of Pulmonary Arterial Hypertension (PAH), created with Sugen5416 and chronic hypoxia, is known to have similar histological findings to those of PAH patients.

Objective: To evaluate the pathophysiological mechanisms of cardiac remodeling due to hypoxic stress with Sugen5416 in vivo.

Methods: Male Sprague-Dawley rats were exposed to hypoxia (10 ± 1% O2) for 2 weeks after a single injection of Sugen5416 (SU-hypoxia group) or the vehicle (V-hypoxia group).

Results: Hypoxia elevated right ventricular (RV) systolic pressure and caused RV remodeling on Day 14. By electron microscopy, metamorphosis of capillaries with endothelial cell occlusive degeneration was observed in the RV myocardium of the SU-hypoxia group from Day 3. After reoxygenation, progressive RV remodeling with extensive degeneration of cardiomyocytes was observed in the SUhypoxia group, associated with a significant increase of oxidative stress and TUNEL-positive cells in both RV and left ventricular myocardium on Day 84. The expression of VEGF mRNA in the RV myocardium was significantly suppressed in the SU-hypoxia group on Day 3, whereas delayed activation of VEGF/extracellular signal-regulated kinase (ERK) signaling pathway on Day 14 were observed.

Conclusion: Capillary degeneration and activation of VEGF/ERK signaling pathway might be crucial to accelerate the cardiac remodeling due to hypoxic stress with Sugen5416.

Keywords:

Sugen5416 (semaxinib), pulmonary arterial hypertension, hypoxia, capillary, cardiac remodeling, vascular endothelial growth factor, ultrastructure, VEGF/ERK signaling pathway.

Affiliation:

Department of Thoracic and Cardiovascular Surgery, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, Takatsuki 569-1094, Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, Takatsuki 569-1094, Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, Takatsuki 569-1094, Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, Takatsuki 569-1094, Department of Pathology, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Department of Cardiovascular Medicine, Osaka City University, Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Department of Pharmacology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Department of Cardiovascular Medicine, Osaka City University, Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Department of Thoracic and Cardiovascular Surgery, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Laboratory of Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094

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