Importance of tumor suppressor gene p53-mediated endothelial cell apoptosis for cardiac angiogenesis and hypertrophy

摘要: Cardiac hypertrophy initially develops as adaptive response of the heart to increased workload, but may progress organ dysfunction if continued over long term. Previous studies suggested that rarefication cardiac endothelial cells be causally involved in development failure. The aim this study was examine whether prevention cell apoptosis, achieved by deletion tumor suppressor gene p53, improve remodelling afterload and prevent or postpone transition Mice with cell-specific p53 (End.p53-KO) were generated crossing p53flox/flox mice expressing Cre recombinase under control tamoxifen-inducible, promoter Tie2 (Tie2.ERT.Cre). induced using transaortic constriction (TAC) model. In mice, accompanied protein expression (P<0.05 vs. sham) elevated levels apoptosis (P<0.01), shown TUNEL activated caspase-3 staining. contrast, reduced apoptotic numbers detected hearts End.p53-KO after TAC (P<0.01 controls). Moreover, exhibited capillary density (P<0.001) higher number lectin-perfused blood vessels (P=0.0002). Endothelial also improved extracardiac angiogenesis unilateral hindlimb ischaemia model associated enhanced reperfusion (P<0.001). vitro analyses confirmed inhibition transient reduction preincubation human microvascular pifithrin-α p53-specific small interfering RNAs, promoted sprouting (P<0.05). addition angiogenesis, less interstitial fibrosis compared those controls expressed lower mRNA p53-regulated target genes extracellular matrix (including collagen, CTGF PAI-1). Importantly, echocardiographical measurements revealed severe fractional shortening controls) better survival 20 weeks TAC. Taken together, our findings reveal accumulation contributes during death failure chronic elevations afterload.