MG53 suppresses NF-κB activation to mitigate age-related heart failure.

Xiaoliang Wang,Xiuchun Li,Hua Zhu,Ki Ho Park,Zehua Bian,Erin Haggard,Chuanxi Cai,Robert E Merritt,Lei Cao,Nahush A Mokadam,Hannah Ong,Paul M Janssen,Xunchang Zou,Tao Tan,Jianjie Ma,Timothy M Pawlik,Bryan A Whitson

doi:10.1172/jci.insight.148375

Abstract

Aging is associated with chronic oxidative stress and inflammation that affect tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here, we demonstrate that the expression of MG53 was reduced in failing human hearts and aged mouse hearts, concomitant with elevated NF-κB activation. We evaluated the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements revealed beneficial effects of rhMG53 treatment in improving heart function of aged mice. Biochemical and histological studies demonstrated that the cardioprotective effects of rhMG53 are linked to suppression of NF-κB–mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administration of rhMG53 in aged mice did not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.

Highlights

Chronic loss of cardiomyocyte integrity underlies human heart failure (HF) associated with aging that often involves progression of acute myocardial infarction (MI) and the maladaptive response of cardiomyopathy [1]
We show that the expression of MG53 is decreased in both the failing human heart and the aged mouse heart, which is accompanied by elevation of NF-κB activation
We demonstrate that repetitive recombinant human MG53 (rhMG53) administration in aged mice is safe and effective in reducing apoptotic cardiomyocyte death and suppressing the chronic inflammation mediated by NF-κB

Summary

Introduction

Chronic loss of cardiomyocyte integrity underlies human heart failure (HF) associated with aging that often involves progression of acute myocardial infarction (MI) and the maladaptive response of cardiomyopathy [1]. Chronic oxidative stress and inflammation associated with aging can render the cardiomyocytes more susceptible to stress-induced MI. Mice without the MG53 gene develop cardiac pathology due to defective membrane repair and increased susceptibility to cardiac injury [7, 8]. We have demonstrated that intravenous administration of recombinant human MG53 (rhMG53) protein could protect against acute heart injury in rodent and porcine models of ischemia-reperfusion– induced MI [5, 10], whether rhMG53 has beneficial effects on chronic HF remains to be determined

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Results

Conclusion