Growth Hormone Releasing Hormone Agonists Improve Heart Function In Mice

PART Ⅰ Improvement of cardiac and systemic functions in old mice by an agonist of growth hormone-releasing hormonePurpose:Potent synthetic agonists of growth hormone-releasing hormone(GHRH)exhibit several favorable effects on heart function and remodeling.Here we assessed whether GHRH agonist MR409 can modulate heart function and systemic parameters in old mice.Methods and results:Starting at the age of 15 months,mice were inj ected subcutaneously with MR409(10μg/mouse/day,n=8)or vehicle(n=7)daily for a total of 6 months.Echocardiography and body weights were measured at baseline and 5 months after treatment.Mice treated with MR409 showed improvments in exercise activity,cardiac function,survival rate,immune function,and hair growth in comparison with controls.More stem cell colonies could be grown out of the bone marrow recovered from the MR409-treated mice.Mitochondrial functions of the hearts of mice treated with MR409 were also significantly improved with more mitochondrial fusion.Fewer β-gal positive cells were observed in endothelial cells(ECs)after 10 passages with MR409.In Doxorubicin(DOX)-treated H9C2 cardiomyocytes,cell senescence marker p21 and reactive oxygen species were significantly reduced after cultured with MR409.MR409 also improved cellular ATP production and oxygen consumption rate in Dox-treated H9C2 cells.Mitochondrial protein OPA1 long isoform was significantly increased after treatment with MR409.Such effect could be blocked by GHRH antagonist MIA602 or PKA inhibitor H89,indicating the involvement of GHRH-R/cAMP/PKA pathway.Conclusions:In short,GHRH agonist MR409 can reverse the aging-associated changes with respect of heart function,mobility,hair growth,cellular energy production and senescence biomarkers.The improvement of heart function may be related to a better mitochondrial functions through GHRH receptor/cAMP/PKA/OPA1 signaling pathway.PART Ⅱ A ROS responsive and peptide targeting Nano therapy for myocardial infarctionPurpose:Growth hormone-releasing hormone(GHRH)agonists holds great potential for treating injured heart after myocardial infarction(MI),in a potential signaling pathway based on GHRH receptors in the heart.However,the effective at-site delivery of GHRH agonists is a great challenge.Methods and results:we describe a self-assembly of ROS responsive poly(propylene sulfide)-poly(ethylene glycol)(PPS-PES)amphiphilic polymers.Hydrophilic peptide GHRH agonists(MR409)were loaded in the inner core of the vesicles(PPS-PEG@MR409).Hydrophobic interactions of propylene sulphide backbones sever to multiply the stability of our drugs,endowing it with potent in vivo stability,while ROS was shown to trigger the drug release by in situ oxidation of PPS from hydrophobic thioether to sulfoxide and finally hydrophilic sulfone results in efficient release of cargo drugs.In vitro,we used hypoxia-ischemia 24 hours to simulate the damage of myocardial cells after MI.Flow cytometry experiments show that PP S-PEG@MR409 can reduce ROS and cardiomyocytes apoptosis;in vivo animal studies show that tail vein injection of PPSPEG@MR409 two hours after myocardial infarction has better cardiac targeting ability.On the basis of reducing the number of injections(once every 3 days),PPSPEG@MR409 group has the same effect as MR409 group(once a day)in reducing the degree of fibrosis after myocardial infarction.Conclusions:Consequently,our results demonstrate the developed PPS-PEG@MR409 nanomedicine may have great potential for cardiac protection after MI,and provide a robust and newly platform for target peptide therapy.