MG53 Acts to Suppress Inflammatory Signaling in Heart Tissue, but Levels Fall with Age
Changes in the regulation of inflammatory signaling in aging is just as complicated as any other aspect of the metabolic shifts that occur with age. A raised level of chronic inflammation is very definitely a bad thing, and contributes to the onset and progression of all of the common age-related conditions. It isn't clear that regulators of inflammation are the right place to intervene, versus deeper causes that provoke the regulators into action, however. The aging body generates a far greater level of prompts that rouse the immune system into inflammation, in comparison to a young body, a range of consequences of cellular damage and dysfunction that could themselves be targets for repair-based therapies. Removal of lingering senescent cells, for example, which secrete pro-inflammatory cytokines and are shown to produce chronic inflammation.
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. During MI, the membrane repair function of cardiomyocytes is compromised, and protection of membrane integrity is an important strategy to treat MI and HF. In addition, chronic oxidative stress and inflammation associated with aging can render the cardiomyocytes more susceptible to stress-induced MI. Therefore, a therapeutic approach that restores tissue integrity and mitigates inflammation can potentially be an effective means to treat age-related organ dysfunction.
We previously identified MG53 as an essential component of cell membrane repair. MG53 nucleates the assembly of the membrane repair machinery in a redox-dependent manner. Mice without the MG53 gene develop cardiac pathology due to defective membrane repair and increased susceptibility to cardiac injury. Transgenic mice with sustained elevation of MG53 in the bloodstream (~100 fold higher circulating MG53 vs wild type mice) lived a healthier and longer lifespan compared with the littermate wild type mice, and displayed increased tissue healing and regeneration capacity following injury. While 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, whether rhMG53 has beneficial effects on chronic HF remains to be determined.
Here we demonstrate that the expression of MG53 is reduced in failing human heart and aging mouse heart, concomitant with elevated NFκB activation. We evaluate the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements reveal beneficial effects of rhMG53 treatment in improving heart function of aging mice. Biochemical and histological studies demonstrate the cardioprotective effects of rhMG53 are linked to suppression of NFκB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administrations of rhMG53 in aged mice do 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.