Mechanisms Of Mesenchvmal Stem Cell-Derived Exosome Mediated Delay Of Cardiac Aging Through MALAT1

Cardiac aging is an important factor that induces cardiovascular diseases.With the increase in the aging population,the risk of developing cardiac aging is also increasing.The specific mechanisms of cardiac aging remain largely unknown,and there is no effective treatment strategy.Therefore,further understanding of specific mechanisms mediating cardiac aging is the first step toward the development of new therapies.Oxidative stress and inflammation play important roles in the senescence process.The aim of this study 1s to determine the roles of exosomes in cardiac aging and the underlying mechanisms.Exosomes are small vesicles secreted by cells.Current studies have found that Exo can repair ischemia induced myocardium injury although the mechanisms remain unknown.We investigated the role of Exo in cardiac aging by injecting Exo into tail vein,and the specific mechanisms of Exo in delaying cardiac cell aging was explored.We examined the changes of heart function and the exercise ability of youngs middle age and old mice and found that the heart function?exercise ability decreased while inflammation increased with aging.We also found that cardiac aging has already started in middle aged mice.Therefore,we used middle aged mice as the aging model.Our data showed that cardiac function,exercise ability increased while the expression of aging and inflammation related genes decreased six weeks after injecting Exo into the tail vein of the mice.We also found that the activity of NF-?B signaling pathway was significantly inhibited by Exo injection.These results suggest that Exo can inhibit inflammatory responses and delay heart aging.Aging can activate the NF-?B signaling pathway,which subsequently triggers the expression of inflammatory cytokines such as TNF-?.It has been shown that IncRNA is in the aging process.Our initial screening identified IncRNA MALATI as a specific IneRNA associated heart aging process.We further showed that MALAT1 is highly expressed in UMSCs(Umbilical Cord Mesenchymal Stem Cells)and Exo.Using D-gal induced aging model,we demonstrated that the beneficial effect of Exo was reduced when MALAT1 was knockout from Exo.These findings were confirmed by our in vitro model of cardiac aging.Our data showed that H2O2 induced H9C2 cardiomyocytes senescence can be prevented by Exo.However,siMALAT1-Exo was not able to suppress NF-?B activation and the expression of TNF-? in the absence of MALAT1.Through bioinformatic analysis and nucleus extraction separation experiments,we found Exo carried MALAT1 could enter the nucleus of H9C2 and delay cell senescence by binding to p65 protein and inhibiting the expression of TNF-?.NLRP3 inflammasome has been implicated in the pathogenesis of aging.We found that NLRP3,Caspase-1 and IL-1? mRNA expression were increased in aged mice.We further demonstrated that Exo could inhibit the mRNA expression of NLRP3?Caspase-1 and IL-1? although the underlying mechanisms remain to be explored.Conclusion:Our study proves that aging intervention in middle age is an effective strategy,which opened a new door for delaying cardiac aging.We demonstrated that Exo can inhibit inflammation and delay aging by releasing MALAT1.In addition,our results also showed that Exo can inhibit the activation of NLRP3,and provide a new therapeutic strategy to inhibit inflammation.