Hye-Yoon Jeon1, Jae-Ah Seo1, Se-Hui Jung1, Yeon-Ju Lee1, Eun-Taek Han2, Won Sun Park3, Seok-Ho Hong4, Young-Myeong Kim1, Kwon-Soo Ha5. 1. Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do 24341, Republic of Korea. 2. Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon, Kangwon-do 24341, Republic of Korea. 3. Department of Physiology, Kangwon National University School of Medicine, Chuncheon, Kangwon-do 24341, Republic of Korea. 4. Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Kangwon-do 24341, Republic of Korea. 5. Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do 24341, Republic of Korea. Electronic address: ksha@kangwon.ac.kr.
Abstract
AIMS: Insulin is a central peptide hormone required for carbohydrate metabolism; however, its role in diabetes-associated pulmonary disease is unknown. Here, we investigated the preventative effect of insulin against hyperglycemia-induced pulmonary vascular leakage and its molecular mechanism of action in the lungs of diabetic mice. MAIN METHODS: Vascular endothelial growth factor (VEGF) activated transglutaminase 2 (TGase2) by sequentially elevating intracellular Ca2+ and reactive oxygen species (ROS) levels in primary human pulmonary microvascular endothelial cells (HPMVECs). KEY FINDINGS: Insulin inhibited VEGF-induced TGase2 activation, but did not affect intracellular Ca2+ elevation and ROS generation. Insulin prevented VEGF-induced vascular leakage by inhibiting TGase2-mediated c-Src phosphorylation, disassembly of VE-cadherin and β-catenin, and stress fiber formation. Insulin replacement therapy prevented hyperglycemia-induced TGase2 activation, but not ROS generation, in the lungs of diabetic mice. Insulin also prevented vascular leakage and cancer metastasis in the diabetic lung. Notably, vascular leakage was not detectable in the lungs of TGase2-null (Tgm2-/-) diabetic mice. SIGNIFICANCE: These findings demonstrate that insulin prevents hyperglycemia-induced pulmonary vascular leakage in diabetic mice by inhibiting VEGF-induced TGase2 activation rather than ROS generation.
AIMS: Insulin is a central peptide hormone required for carbohydrate metabolism; however, its role in diabetes-associated pulmonary disease is unknown. Here, we investigated the preventative effect of insulin against hyperglycemia-induced pulmonary vascular leakage and its molecular mechanism of action in the lungs of diabeticmice. MAIN METHODS:Vascular endothelial growth factor (VEGF) activated transglutaminase 2 (TGase2) by sequentially elevating intracellular Ca2+ and reactive oxygen species (ROS) levels in primary human pulmonary microvascular endothelial cells (HPMVECs). KEY FINDINGS: Insulin inhibited VEGF-induced TGase2 activation, but did not affect intracellular Ca2+ elevation and ROS generation. Insulin prevented VEGF-induced vascular leakage by inhibiting TGase2-mediated c-Src phosphorylation, disassembly of VE-cadherin and β-catenin, and stress fiber formation. Insulin replacement therapy prevented hyperglycemia-induced TGase2 activation, but not ROS generation, in the lungs of diabeticmice. Insulin also prevented vascular leakage and cancer metastasis in the diabetic lung. Notably, vascular leakage was not detectable in the lungs of TGase2-null (Tgm2-/-) diabeticmice. SIGNIFICANCE: These findings demonstrate that insulin prevents hyperglycemia-induced pulmonary vascular leakage in diabeticmice by inhibiting VEGF-induced TGase2 activation rather than ROS generation.
Authors: Chinmayee D Bhedi; Sabina Nasirova; Deniz Toksoz; Rod R Warburton; Kevin J Morine; Navin K Kapur; Jonas B Galper; Ioana R Preston; Nicholas S Hill; Barry L Fanburg; Krishna C Penumatsa Journal: FASEB J Date: 2019-11-28 Impact factor: 5.191