p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload

Abstract

Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.

Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: the critical role of ASK1 and VEGF

“…[7][8][9][10] However, prolonged cardiac hypertrophy leads to cardiac ischemia as a result of the reduction in myocardial capillary density. This reduction is one of Low Na Veh Hyd Irb Tem Figure 5 Effect of hydralazine, tempol and irbesartan on cardiacVEGF (a) and phospho-ASK1 (b) of DS rats.…”

“…[7][8][9][10] Blocking VEGF leads to a decrease in myocardial capillary density in pressure overload-induced cardiac hypertrophy models, resulting in the transition from compensated to decompensated cardiac hypertrophy and thus leading to the development of heart failure. 10 Moreover, pressure overload-induced cardiac hypertrophy in VEGF-deficient mice leads to a reduction in myocardial capillary density, which then accelerates the transition from compensated myocardial hypertrophy to heart failure.…”

“…[7][8][9][10] Therefore, recent work has focused on examining the regulatory mechanisms of capillary density in cardiac hypertrophy. However, the role of angiotensin II in the regulation of capillary density during cardiac hypertrophy is still unclear.…”

Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

“…VEGF has been extensively studied regarding its effect on cell growth and proliferation. In the cardiomyocytes, VEGF also is required for cell growth [22][23][24]. Studies in vivo have shown that a decoy VEGF receptor blocked cardiac growth induced by Akt1 activation [4,16].…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…Interestingly, inhibition of the normal angiogenic response to pressure overload was recently shown to be mediated by the upregulation of p53 (REF. 82), raising concerns about strategies that might increase the activity of p53 in the heart (REF. 83), particularly in hypertensive patients.…”