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

Abstract

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-α/iNOS), calcium overload index (TRPC1, 2, 4, 6), apoptosis (mitochondrial BAX, cleaved caspase 3/PARP), fibrosis (Smad3/TGF-β), hypoxic (HIF-1α), DNA damage (γ-H2AX) and endothelial function (eNOS/ET-1R), as well as in lung injury score, number of muscularized vessels in lungs, number of TRPC1 + and HIF-1α + cells in pulmonary artery, and number of γ-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 shamoperated mice, TAC mice to TAC+SS-31 mice. Conclusion: Antioxidant peptide SS-31 administration effectively attenuates TAC-induced PAH in mice.

Pharmacometabolic response to pirfenidone in pulmonary fibrosis detected by MALDI-FTICR-MSI

“…Interestingly, we found unchanged levels of glutathione and glutathione disulfide in bleomycin-induced pulmonary fibrosis, whereas these are increased in pirfenidone-treated IPF patients. In mice, levels of glutathione and glutathione disulfide are suppressed by overexpression of TGF-β [35]. We speculate that recovery of glutathione and glutathione disulfide levels in IPF might indicate a role for pirfenidone in modulating the redox imbalance that contributes to persistent fibrosis [36].…”

Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study

“…This supports previous findings that bleomycin activates the oxidative stress response in the bleomycin-induced mouse lung fibrosis model and upregulates GSH. Liu et al 36 also found that GSH levels were initially suppressed by overexpression of TGF-beta in mouse lungs, but later returned to normal, possibly implicating GSH in a response to fibrosis. Our findings may therefore reflect the body’s attempt to generate more GSH as part of the oxidative stress response in IPF.…”

Insights into the pulmonary vascular complications of heart failure with preserved ejection fraction

“…; Lu et al . ). In addition, elevated NT‐proBNP plasma levels, alveolar–capillary wall thickening and perivascular fluid cuff formation along extra‐alveolar vessels were observed in a recently established aortic‐banded cat model of PH‐HFpEF (Wallner et al .…”