Abstract 9851: Benefit of Antioxidant Peptide SS-31 Treatment in Attenuating Transverse Aortic Constriction-Induced Pulmonary Arterial Hypertension in Mice

Abstract

Introduction: We investigated the effect of mitochondria-targeted antioxidant peptide SS-31 on transthoracic aortic constriction (TAC)-induced pulmonary arterial hypertension (PAH) in mice. Methods and Results: Adult-male mice (n=36) were equally divided into group 1 (sham-control), group 2 (TAC only), and group 3 (TAC-SS-31, 2 mg intra-peritoneal injection/day). By day 60, right ventricular systolic blood pressure (RVSBP) was measured prior to sacrificing the animals and the right heart and lung tissues were later collected. RVSBP was significantly higher in group 2 than in group 1, but the elevation was substantially suppressed in group 3 (p<0.0001). Pulmonary protein expressions of oxidative-stress ((NOX-1, NOX-2, oxidized protein), cytosolic cytochrome-C, inflammation (MMP-9, TNF-α, NF-κB), calcium-overload-index (TRPC1, 2, 4, 6), apoptotic (mitochondrial BAX, cleaved caspase 3 and PARP), fibrotic (Smad3, TGF-β), hypoxic (HIF-1α), DNA-damage (γ-H2AX), and endothelial function-related (eNOS, ET-1R) biomarkers showed an identical pattern, whereas the anti-fibrotic (Smad1/5, BMP-2) markers and number of small vessels showed an opposite pattern compared to that of RVSBP among the three groups (all p<0.001). The lung injury score, number of muscularized vessels in lungs, cellular expressions in PA (TRPC1+, HIF-1α+) and in lung parenchyma (γ-H2AX+, Ki-67+), showed an identical pattern, whereas the number of alveolar sacs showed an opposite pattern of RVSBP among the three groups (all p<0.001). The protein expressions of anti-oxidants (HO-1, NQO 1, GR, GPx) were significantly progressively increased from groups 1 to 3 (all p<0.001). Conclusion: Antioxidant peptide SS-31 effectively attenuated TAC-induced PAH in a murine model.