Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice

作者：Lu, Hung i; Huang, Tien hung; Sung, Pei hsun; Chen, Yung lung; Chua, Sarah; Chai, Han yan; Chung, Sheng ying; Liu, Chu feng; Sun, Cheuk kwan; Chang, Hsueh wen; Zhen, Yen yi; Lee, Fan yen^*; Yip, Hon kan^*

来源：Acta Pharmacologica Sinica, 2016, 37(5): 589-603.

DOI：10.1038/aps.2015.162

• antioxidant peptide SS-31
• mitochondria-targeted
• pulmonary arterial hypertension
• transverse aortic constriction
• ROS
• inflammation
• apoptosis

Aim: Antioxidant peptide SS-31 is a class of cell-permeable small peptides, which selectively resides on the inner mito-chondrial membrane and possesses intrinsic mitochondrial protective capacities. In this study we investigated the therapeutic effects of antioxidant peptide SS-31 on transverse aortic constriction (TAC)-induced pulmonary arterial hypertension (PAH) in a murine model.
Methods: Adult male mice were divided into 3 groups: sham-operated mice, TAC mice, and TAC SS-31 mice that underwent TAC surgery and received SS-31 (2 mg/d, ip) for 60 d. The right ventricular systolic blood pressure (RVSBP) was measured on d 60 prior to sacrificing the mice; then their right heart and lung tissues were collected for histological and biochemical examinations. Lung injury scores were defined by the increased crowded area and decreased number of alveolar sacs.
Results: TAC mice showed significantly higher RVSBP compared with sham-operated mice, the elevation was substantially suppressed in TAC SS-31 mice. The same pattern of changes was found in pulmonary levels of oxidative stress proteins (NOX-1/NOX-2/oxidized proteins), cytosolic cytochrome c, biomarkers related to inflammation (MMP-9/TNF-alpha/iNOS), calcium overload index (TRPC1, 2, 4, 6), apoptosis (mitochondrial BAX, cleaved caspase 3/PARP), fibrosis (Smad3/TGF-beta), hypoxic (HIF-1 alpha), DNA damage (gamma-H2AX) and endothelial eNOS/ET-1R), as well as in lung injury score, number of muscularized vessels in lungs, number of TRPC1( ) and HIF-1 alpha( ) cells in pulmonary artery, and number of gamma-H2AX( ) and Ki-67( ) cells in lung parenchyma. An opposite pattern of changes was observed in pulmonary anti-fibrotic markers (Smad1/5, BMP-2), number of small vessels, and number of alveolar sacs. In contrast, the levels of antioxidant proteins (HO-1/NQO-1/GR/GPx) in lung parenchyma were progressively and significantly increased from sham-operated mice, TAC mice to TAC SS-31 mice.
Conclusion: Antioxidant peptide SS-31 administration effectively attenuates TAC-induced PAH in mice.

• 出版日期2016-5
• 单位中国医科大学; 长春大学; 中山大学