Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis

Abstract

Elevated tumor suppressor p53 expression has been associated with heart diseases, including the diabetic heart. However, its precise role in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. We hypothesized that the development of DCM is attributed to up-regulated p53-mediated both early cardiac cell death and persistent cell senescence, glycolytic and angiogenetic dysfunctions. The present study investigated the effect of p53 inhibition with its specific inhibitor pifithrin-α (PFT-α) on the pathogenesis of DCM and its associated mechanisms. Type 1 diabetes was induced with multiple low doses of streptozotocin. Both hyperglycemic and age-matched control mice were treated with and without PFT-α five times a week for 2 months and then sacrificed at 3 and 6 months post-diabetes. Treatment with PFT-α significantly prevented the progression of diabetes-induced cardiac remodeling and dysfunction (i.e., DCM). Mechanistically, the inhibition of p53 prevented the cardiac apoptosis during early-stage diabetes (0.5 month), attenuated diabetes-induced cell senescence (3 and 6 months), and improved both glycolytic and angiogenic defects by increasing hypoxia-induced factor (HIF)-1α protein stability and upregulating HIF-1α transcription of specific target genes at 3 and 6 months after diabetes. Therefore, the targeted inhibition of p53 in diabetic individuals may provide a novel approach for the prevention of DCM.

Comparative Study of the Effects of GLP1 Analog and SGLT2 Inhibitor against Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms

“…Apoptotic cell damage is another mechanism for DCM, in which elevated blood sugar in DM promotes the release of mitochondrial cytochrome C to the cytosol, resulting in activation of caspase-3 and apoptotic cell death of cardiomyocytes [35]. Also, previous studies demonstrated the role of anti-apoptotic p53 protein [36] and proapoptotic Bcl-2 proteins [37] in DCM in diabetic hearts. In the current study, we found significant increase in caspase-3 in myocardial tissues of diabetic rats, suggesting involvement of apoptosis in the development of DCM.…”

Nicorandil alleviates apoptosis in diabetic cardiomyopathy through PI3K/Akt pathway

“…Previous studies have found that apoptosis plays an important role in the progression of diabetic cardiomyopathy. 26,27 Although nicorandil cannot decrease blood glucose directly， it can alleviate the apoptosis in cardiomyocyte resulted from the hyperglycaemia through other pathway. It is known that the production of NO is reduced and eNOS activity is weakened in the environment of hyperglycaemia.…”

Pifithrin-α alters p53 post-translational modifications pattern and differentially inhibits p53 target genes

“…Despite its unclear molecular mechanism and potential off-target effects, PFT-α is still widely used as a specific p53 inhibitor to investigate p53-dependent response, for instance, in autophagy 12 , response to drugs 13 , DNA damage 14 , neurogenesis and angiogenesis 15 or cardiac hypertrophy 16 . As activation of the p53 pathway was recently described to inhibit the CRISPR/Cas system 17,18 , PFT-α was also used in attempts to increase the efficiency of genome editing 19 .…”