Blockage Of Angiotensin-? Signaling Reduces Heart Injury During Weightlessness

Objective:Sending astronauts to farther space and prolonging the duration of space missions will challenge the existing capabilities of space medicine.Weightlessness can cause a series of abnormal reactions,especially myocardial atrophy and dysfunction.However.the mechanisms by which weightlessness causes myocardial atrophy and dysfunction remain not completely clear,and the preventive and therapeutic approaches are limited.In an effort to study the mechanisms underlying weightlessness-induced myocardial atrophy and dysfunction,we compared mRNA expressing profiles in myocardial tissues of sham and tail-suspended mice and found that the expression of multiple genes was altered,among which Apelin and Apelin receptor were the most down-regulated genes in tail-suspended mouse hearts.It is well known that the Apelin/Apelin receptor system antagonizes the Angiotensin ?/Angiotensin ? receptor system,and their balance helps to maintain cell homeostasis.A reduction of the Apelin and Apelin receptor expression may lead to a relative increase in the Angiotensin?/Angiotensin ? receptor system thereby facilitating myocardial injury in weightlessness.Thus,we hypothesized that blockage of the Angiotensin ? signaling under weightlessness could balance the negative effects of downregulation of Apelin/Apelin receptor system thereby protecting the heart from weightlessness-caused injury.Accordingly,we investigated whether and how blockage of Angiotensin ?signaling prevents myocardial atrophy and dysfunction in a mouse model of tail-suspension-simulated weightlessness using losartan,an Angiotensin ? receptor blocker widely used in clinic setting to lower blood pressure.Methods:Sham and tail-suspended male C57BL/6 mice aged 10 weeks were given orally losartan or vehicle for 28 days.The mRNA expressing profiles in myocardial tissues of sham and tail-suspension mice were analyzed by the Agilent SurePrint G3 Mouse GE Microarray(8*60K,Design ID:028005).The mRNA levels of Apelin/Apelin receptor were measured by Real-Time PCR.Cardiac function was assessed by echocardioraphy.Blood pressure was analyzed by the MRBP system.Myocardial tissue sections were stained with wheat germ agglutinin-Hoechst 33342 to determine the cross-sectional area of myocardial cells.Hematoxylin-eosin staining was performed on soleus muscle of hind limbs and the cross-sectional area of muscle cells in hind legs was determined.Oxidative stress was determined by reactive oxygen species production,malondialdehyde and protein carbonyl content.NADPH oxidase activation was determined by analyzing its cytosolic subunits in cell membrane.Western blot was used to detect calpain and muscle atrophy-related protein MuRF1.Results:Comparing the mRNA expressing profiles between sham and tail-suspended mouse hearts identidied Apelin and Apelin receptor as the most down-regulated genes in tail-suspended mouse hearts,which was confirmed by Real-Time PCR.The tail suspension resulted in a reduction of heart weight and cardiomyocyte size,indicative of myocardial atrophy,which was accompanied by decreased systolic and diastolic function.These changes were attenuated by administration of losartan.Losartan lowered diastolic blood pressure in tail-suspended mice.Tail suspension induced the overexpression of MuRF1,increased reactive oxygen species production,malondialdehyde and protein carbonyl content,activated NADPH oxidase and calpain in mouse heart,all of which were prevented by losartan.Conclusions:Administration of losartan inhibits myocardial atrophy and dysfunction inducedby microgravity.Its protective effect may be attributed to the inhibition of MuRF1 overexpression,NADPH oxidase and calpain activation.Thus,blockage of the Angiotensin ?/Angiotensin ? receptor system may be a potential effective approach to prevent and treat myocardial abnormalities caused by weightlessness,which may have some clinical implications.