The Role Of CaN/NFAT Signaling Pathway In Aerobic Exercise-induced Improvement Of Cardiac Hypertrophy In Hypertension

Purpose:Calcineurin/activation T cell factor?CaN/NFAT?signaling pathway plays a key role in the development of intracellular Ca²⁺induced myocardial hypertrophy.A-kinase anchoring proteins?AKAP150?can modulate the signal pathway by combining CaN.This study aims to investigate the mechanism of CaN/NFAT signaling pathway underlying the reversal effect of aerobic exercise on the hypertension-induced cardiac hypertrophy.Methods:Male spontaneously hypertensive rats?SHRs?and Wistar-Kyoto rats?WKYs?,12 weeks age,were randomly separated into a sedentary group?WKY-SED,SHR-SED?,and an exercise group?WKY-EX,SHR-EX?.WKY-SED and SHR-SED were used as normotensive control.Exercise groups were subjected to a 12-week treadmill training protocol:20m/min?about 55-65%of maximal aerobic velocity?,0%grade,60min/day,5d/w.After 12 weeks,body weight,heart rate and systolic blood pressure was acquired of each group.The cardiac function of rats was detected by the Langendorff isolated heart irrigation system,and the myocardial tissue HE staining observed the thickness of the ventricular wall and the morphology of myocardial cells.Immunohistochemical was used to observe the distribution and changing of A-kinase anchoring protein?AKAP150?and CaN in myocardial.Western blot was applied to examine the expression levels of CaN,NFAT,p-NFAT,AKAP150 and GATA4,protein in myocardial.Cell immunofluorescence was perfomed to study the space distribution and co-localization of CaN and AKAP150 in myocardial cells.Results:?1?After 12 weeks of aerobic exercise,the heart rate?HR?and systolic blood pressure?SBP?in the SHR-SED group were significantly higher than that in the WKY-SED group?P<0.01?,and the SHR-EX group BW,HR and SBP were significantly lower than the SHR-SED group?P<0.01?.?2?Langendorff isolated heart irrigation:compared with the WKY-SED group,the SHR-SED group was reduced by+dp/dt_max?P<0.05?.After 12 weeks of aerobic exercise,the SHR-EX group was compared with the SHR-SED group,with the increase of+dp/dt_max?P<0.05?,-dp/dt_max was reduction?P<0.01?,the LVSP and LVSP-LVDP were both remarkable elevation?P<0.01?.?3?HE staining:the SHR-SED group was more loosely arranged than the myocardial cells in the WKY-SED group,with the occasional fiber fracture,and the area of the individual cells were increased significantly.The SHR-EX group was more orderly and dense than the SHR-SED group,and the cross-sectional area and diameter of the cells were also decreased.?4?Immunohistochemistry:CaN and AKAP150 positive immunoactivity for the SHR-SED group were significantly higher than that in the WKY-SED group?P<0.01?.After 12 weeks of aerobic exercise,the CaN positive immunoactivity of the SHR-EX group was significantly lower than that of the SHR-SED group?P<0.01?,and the AKAP150 positive immunoactivity of the SHR-EX group was significantly higher than that of the SHR-SED group?P<0.01?.?5?The fluorescence intensity of CaN and AKAP150 in the SHR-SED group were higher than WKY-SED group?P<0.01?,and the fluorescence intensity of the SHR-EX group AKAP150 was higher than SHR-SED group?P<0.01?,and the expression of CaN was lower than the SHR-SED group?P<0.01?.?6?The protein expression of CaN and AKAP150 in the SHR-SED group were higher than that in the WKY-SED group?P<0.01?.The expression of p-NFAT in the SHR-SED group was significantly lower than that the WKY-SED group.The expression of the SHR-EX group CaN was lower than the SHR-SED group?P<0.01?,and the expression of p-NFAT and AKAP150 was higher than that in the SHR-SED group.Conclusion:Aerobic exercise reduces the activity of the CaN/NFAT signaling pathway and increases the expression of AKAP150 in the SHR myocardial,which is one of the molecular mechanisms to improve the hypertrophy of the heart.