Clearance Of The Senescent Myocardial Cell By Abt263 Ameliorates Ventricular Remodeling In Rat Cardiac Dysfunction Model

Background:Senescense is universal biological issue accompanying systematic degeneration and organ dysfunction.The morbidity of desease relative to senescense are increasing along with the process of ageing,expecailly in cardiovascular disease.Thus,it will be catastrophic that we take no account of potential relationship between the senescense and disease development,such as atherosclerosis,heart failure and arrhythmia,etc.The senescent cardiac myocyte contributes to the heart failure with the symptom of decreasing cardiac output and systolic dysfunction.Senescent cells are accumulated and difficulty clear out in organ in the reason of the Bcl-2 signature modification and SASP effect,which impair the tissue structure and local function.Increasing studies manifested that clearance of the senescent cell can improve the function in different system.Aim:To discover the mechanism and benefit of clearance of the senescent myocardial cells by abt263 could improve the ventricular remodeling and cardiac function.Methods and results:In vitro,Ang Ⅱ could accelerate the neo-myocardial cell senescense by the SA-β-GAL staining,53.23±5.19%vs.6.34±1.40%,P<0.01.We found that Bcl-2,Bcl-w,Bcl-xl,MCL-1 and p16Ink4a was significantly incrasing in mc-s and mc/AngⅡ,respectively comparing to group mc and mc/ctrl,P<0.01.TUNEL stain showed the higher apoptosis rate in mc-s/abt263 than mc-s/ctrl and mc/abt263 group,P<0.01.Annexin-V/PI result was consistent with TUNEL.The rate of p16Ink4a was significantly decreasing in group mc-s/abt263 than mc-s/ctrl,P<0.01.meanwhile,we didn’t find the difference in group mc/abt263,mc-s/ctrl and mc group.Intervention of Bcl-w,Bcl-2 and MCL1 didn’t disturb the effect of abt263 on senescent and non-senescent cells.However,modification of Bcl-xl affect the abt263 function.The cell viability was decreasing in group mc/lenti-Bcl-xl than mc/Mock treated with abt263,P<0.01.Addtionally,the viability and the senescent cell ratio were increasing in gourp mc-s/siBcl-xl than mc-s/ctr1,P<0.01.In the result of Transwell culture,we can find the SA-β-Galpositiverate,p16 positive cell ratio and CSA were decreasing in group mc+mc-s/TBRi than mc+mc-s/ctrl,P<0.01 and SerCa2+ATPase activity and cell viability were increasing,P<0.01.Intriguingly,TBRi can inhibit the Smad-3 phosphorylation and Nox4 expression.At the same time,recombinant TGF-β1 couldincrease Nox4 expression.ROS could be repressed in group mc+mc-s/TBRi.In vivo,the ratio of apoptosis was higher in Taac/abt263,however with down-regulation of fibrosis rate,hypertrophy and LW/BW,P<0.01.Meanwhile,EF,FS and Vmax were significantly improved in group Taac/abt263 with better survival rate,P<0.01.Conclusion:1,AngⅡ accelerates the senescence of neonatal myocardial cells,meanwhile,Bcl-2 expression signature modified by AngⅡ are similar to the non-induced senescence group.Abt263 could induce senescent neonatal myocardial cells apoptosis rather than non-senscent counterpart.2,Senescent associated protein expression are similar in TAAC and aging rat.Abt263 could eliminate p16Ink4a positive cells and improve the interstitial fibrosis and hypertrophy,which enhances the ventricular function.3.Bcl-xl play a core role in abt263 targeting effect on senescent myocardial cells.Inhibition of TGF-β/Smad3/Nox4 could abate the ROS in senescent cell.