Effects of a novel peptide Ac-SDKP in radiation-induced coronary endothelial damage and resting myocardial blood flow

Umesh C Sharma,Saraswati Pokharel,Min Chen,Joseph A Spernyak,Shirley Xu,Supriya D Mahajan,Andrew Baird,Swati D Sonkawade,Steven G Turowski,Adrienne Groman,Sandra Sexton,Anurag K Singh

doi:10.1186/s40959-018-0034-1

Abstract

BackgroundCancer survivors treated with thoracic ionizing radiation are at higher risk of premature death due to myocardial ischemia. No therapy is currently available to prevent or mitigate these effects. We tested the hypothesis that an endogenous tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) counteracts radiation-induced coronary vascular fibrosis and endothelial cell loss and preserves myocardial blood flow.MethodsWe examined a rat model with external-beam-radiation exposure to the cardiac silhouette. We treated a subgroup of irradiated rats with subcutaneous Ac-SDKP for 18-weeks. We performed cardiac MRI with Gadolinium contrast to examine resting myocardial blood flow content. Upon sacrifice, we examined coronary endothelial-cell-density, fibrosis, apoptosis and endothelial tight-junction proteins (TJP). In vitro, we examined Ac-SDKP uptake by the endothelial cells and tested its effects on radiation-induced reactive oxygen species (ROS) generation. In vivo, we injected labeled Ac-SDKP intravenously and examined its endothelial localization after 4-h.ResultsWe found that radiation exposure led to reduced resting myocardial blood flow content. There was concomitant endothelial cell loss and coronary fibrosis. Smaller vessels and capillaries showed more severe changes than larger vessels. Real-time PCR and confocal microscopy showed radiation-induced loss of TJ proteins including- claudin-1 and junctional adhesion molecule-2 (JAM-2). Ac-SDKP normalized myocardial blood flow content, inhibited endothelial cell loss, reduced coronary fibrosis and restored TJ-assembly. In vitro, Ac-SDKP localized to endothelial cells and inhibited radiation-induced endothelial ROS generation. In vivo, labeled Ac-SDKP was visualized into the endothelium 4-h after the intravenous injection.ConclusionsWe concluded that Ac-SDKP has protective effects against radiation-induced reduction of myocardial blood flow. Such protective effects are likely mediated by neutralization of ROS-mediated injury, preservation of endothelial integrity and inhibition of fibrosis. This demonstrates a strong therapeutic potential of Ac-SDKP to counteract radiotherapy-induced coronary disease.

Highlights

The success of cancer radiotherapy, developed over decades for the most aggressive forms of cancers, has led to the application of this treatment modality to more than 50% of the cancer patients. [1,2,3]
Compared to non-radiated baseline controls, thoracic radiation exposure led to reduction of midmyocardial blood flow content as demonstrated by reduced signal intensities after Gadolinium infusion (Fig. 1 a & b)
The signal intensity at the Y-intercept was comparable to those of normal controls in Ac-SDKP treated rats, which is consistent with preserved myocardial blood flow content after chronic Ac-SDKP therapy

Summary

Introduction

The success of cancer radiotherapy, developed over decades for the most aggressive forms of cancers, has led to the application of this treatment modality to more than 50% of the cancer patients. [1,2,3]. The success of cancer radiotherapy, developed over decades for the most aggressive forms of cancers, has led to the application of this treatment modality to more than 50% of the cancer patients. With millions of patients surviving cancer over the last decade, use of radiotherapy is a clinical reality, raising hope for patients with aggressive and life-threatening tumors [4]. Premature coronary artery and cardiovascular diseases have created an unanticipated risk of late morbidity and mortality [5]. The only available clinical solution is “dose reduction” of radiation, which may risk local control of the cancer. Despite increased morbidity and mortality associated with radiation-induced cardiovascular disease, no specific therapeutic agents are available to-date to prevent or mitigate these conditions. Cancer survivors treated with thoracic ionizing radiation are at higher risk of premature death due to myocardial ischemia. We tested the hypothesis that an endogenous tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) counteracts radiation-induced coronary vascular fibrosis and endothelial cell loss and preserves myocardial blood flow

Methods

Results

Conclusion