Functional Study of Tumor Suppressor p53 Gene Variation: Effect on Cardiovascular Adaptation to Exercise Training

Abstract

Aerobic exercise capacity is inversely related to CVD risk and all cause mortality. p53 plays a crucial role in mitochondrial DNA (mtDNA) maintenance, which is important for mitochondrial function and disease prevention. Here, we extend this concept and investigate whether the p53 codon 72 R/P polymorphism is associated with the adaptive response to aerobic exercise training (AEXT) with respect to enhancing aerobic capacity. 144 sedentary middle‐aged to older females underwent standardized AEXT for 6‐ month. We observed that R allele‐carriers (RR/RP, n = 117) had two‐fold greater improvement in VO2 max in response to the AEXT compared to the non‐carriers (PP, n = 27) (P < .05). To explore the likely molecular mechanisms of p53 being a potential regulator of cardiovascular adaptation to exercise, we further assessed 1) mitochondrial translocation of p53, 2) p53‐mtDNA binding complex, and 3) mtDNA contents in genotyped HUVEC (n = 10, from ten different donors) exposed to exercise‐simulated high flow shear stress (h‐flow, 20 dyne/cm2, 24 h) in vitro. We observed a dramatic increase in mitochondrial p53 level and p53‐mtDNA binding complex under h‐flow (n = 5). Also, RR/RP HUVEC (n = 7) showed significantly higher mtDNA contents compared to PP HUVEC (n = 3) (P < 0.01). Further molecular genetic mechanisms will be discussed. The findings in this study may provide new insights into physiological role of p53 in CV health.