Mechanisms Of Aerobic Exercise In Improving Left Ventricular Pressure-Overload Hypertrophy

Background:Left ventricular pressure-overload hypertrophy(LVPOH)is an adaptive process of the left ventricle to pathological pressure overload,which is common in patients with hypertension or aortic stenosis.LVPOH is a risk factor for heart failure,atrial fibrillation,stroke,sudden cardiac death,and cardiovascular mortality.LVPOH has several immune responses,manifested by changes in the composition of cardiac immune cell subsets.Regulatory T cells (Tregs)are a subpopulation of CD4~+T cells with important immunomodulatory functions.Adoptive transfer of Tregs can inhibit the activation of macrophages and T cells in the heart and reduce cardiac fibrosis.Aerobic exercise refers to exercise involving dynamic movements of large muscle groups,mainly relying on aerobic metabolism to provide energy for muscle contraction.Regular moderate aerobic exercise is considered beneficial for cardiovascular health and is the cornerstone of cardiac rehabilitation.Aerobic exercise has immunomodulatory effects,but the effect of aerobic exercise on LVPOH is less studied,and whether this effect is related to Treg cells has not been reported.Objective:This study aims to establish an LVPOH model,observe the effect of aerobic exercise on LVPOH,and preliminarily explore the possible mechanisms of aerobic exercise affecting LVPOH,to provide new treatment approaches and basic research evidence for LVPOH.Methods:(1)LVPOH model was induced by abdominal aortic constriction(AAC).Heart weight,ventricular wall thickness,HE staining,and Masson staining were detected at different time points to confirm that the LVPOH model was successfully established,and choose the optimal time point for observation in subsequent experiments.(2)The LVPOH mouse model was established and moderate-intensity aerobic exercise was performed.Aforementioned indexes of cardiac hypertrophy were detected again to confirm whether aerobic exercise could improve LVPOH in mice after AAC.(3)RNA sequencing analysis of the whole heart was performed to explore and screen the key signaling pathways and effector molecules that aerobic exercise improves LVPOH.(4)By detecting Tregs and their related cytokines in the heart,spleen,and peripheral blood,it was confirmed whether the improvement of LVPOH by aerobic exercise was related to Tregs.(5)By detecting the ratio and function of Tregs in peripheral blood of LVPOH patients,it was verified again that LVPOH is related to Tregs.Results:(1)AAC surgery induced LVPOH.The mice with AAC had increased heart weight and heart-to-weight ratio,thickness of diastolic interventricular septum and left ventricular posterior wall,cardiomyocyte cross-sectional area(all P<0.05),and interstitial and perivascular fibrosis in the heart(P>0.05).5 weeks after surgery was the ideal time point for LVPOH observation.(2)Aerobic exercise improved LVPOH.Aerobic exercise significantly reduced heart weight and heart-to-weight ratio,left ventricular wall thickness,cardiomyocyte cross-sectional area(all P<0.05),and fibrosis in AAC mice(P>0.05).(3)Aerobic exercise induced differential expression of genes in AAC hearts.These genes mainly affected biological processes such as T-cell activation,animal organ development,and were involved in signaling pathways such as MAPK,Hippo,PI3K-Akt,and TGF-β,as well as extracellular matrix-receptor and cytokine-cytokine receptor interactions.Among them,several genes were associated with immune inflammatory processes.(4)Aerobic exercise improved the state of cardiac immune inflammation caused by LVPOH.Aerobic exercise decreased CD8~+T cells(19.74%in the AAC group and 15.08%in the AAC+EX group)and increased B cells(0.53%in the AAC group and 2.69%in the AAC+EX group)and Tregs(0.22%in the AAC group and 1.93%in the AAC+EX group)in the heart.In addition,aerobic exercise also elevated Tregs to CD4~+T cell ratio in peripheral blood and spleen(peripheral blood:2.18%in the AAC group,3.17%in the AAC+EX group;spleen:7.96%in the AAC group,9.37%in the AAC+EX group)(all P<0.05).(5)Patients with LVPOH were in an immunoinflammatory state.The percentage of neutrophils increased by 4%(P<0.05),and Tregs were significantly decreased(LVPOH group 3.68%,Control group 5.17%,P<0.001)in the blood.The level of IL-6 in the blood increased(LVPOH group 11.3pg/ml,Control group 6.5pg/ml,P<0.05),while the levels of IL-10 and TGF-βwere significantly decreased(IL-10:LVPOH group 6.1pg/ml,Control group 9.1pg/ml,P<0.05;TGF-β:LVPOH group 37.1pg/ml,Control group 42.95pg/ml,P<0.05).Conclusions:(1)Aerobic exercise improved left ventricular pressure-overload hypertrophy.(2)The effect was related to the increase in the proportion of Tregs.