Abstract 18838: An Endogenous Tetrapeptide N-acetyl-Ser-Asp-Lys-Pro Inhibits Radiation-Induced Myocardial Inflammation and Fibrosis

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Abstract

Introduction: Radiotherapy (RT) is a commonly used adjuvant therapy for thoracic cancers. However, radiation exposure also induces myocardial inflammation and fibrosis. No therapy is currently available to antagonize these effects.

Hypothesis: We tested the hypothesis that a novel tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) counteracts radiation-induced myocardial inflammation and fibrosis. Such protective effects of Ac-SDKP are exerted by inhibiting a pro-inflammatory and pro-fibrotic mediator, galectin-3.

Methods: We generated a rat model of cardiac inflammation and fibrosis by using external beam radiation (30Gy, single-dose). Post radiation, we treated these rats with continuous Ac-SDKP infusion and measured their cardiac function using 4.7T cardiac MRI. On completion of Ac-SDKP therapy, we quantified cardiac fibrosis by trichrome staining, macrophage infiltration by CD68 immunostaining and galectin-3 expression by enzyme-linked immunoassays. We also localized Ac-SDKP binding sites into macrophages using newly synthesized fluorochrome-conjugated Ac-SDKP. We then determined radiation-induced galectin-3 activity and its inhibition by Ac-SDKP, both in vivo and in vitro.

Results: Despite preserved cardiac systolic function, radiation exposure increased macrophage infiltration and myocardial interstitial fibrosis, which were robustly inhibited by chronic Ac-SDKP infusion (macrophage/HPF: Sham, 6±1; radiation, 24±4; Ac-SDKP, 11±2, p<0.001; % fibrosis: Sham, 3.96±0.5; radiation, 9.3±1.6; Ac-SDKP, 4.9±0.8, p<0.001, N=8-10). Such protective effects of Ac-SDKP were accompanied by decrease in radiation-induced galectin-3 activity, both in vivo (radiation, 18.4±3 vs. Ac-SDKP, 7.2±1, p<0.05) and in vitro (radiation, 2.2 ± 0.07 vs. Ac-SDKP, 1.9 ± 0.07, p<0.05). In cultured macrophages, Ac-SDKP binding sites were densely localized to perinuclear region.

Conclusions: Our study provides novel data to show the anti-inflammatory and anti-fibrotic effects of Ac-SDKP in radiation-induced myocardial damage. Such protective effects, at least in part, are exerted by inhibiting galectin-3. This demonstrates a strong therapeutic potential of this endogenous peptide to counteract RT-induced cardiotoxicity.

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