Role of the Tumor Suppressor Gene p53 in Pathogenesis of Maladaptive Cardiac Hypertrophy Following a Pressure-Overloaded State
Introduction. Heart disease and its resulting pathology is the leading cause of death worldwide.1 Cardiovascular mortality can result from overwork of tissue following pressure-overloaded states such as chronic systemic hypertension, pulmonary hypertension, and aortic stenosis. Two of the manifestations of these disease states are maladaptive hypertrophy of the ventricles to compensate for the increase in afterload and defects in vascularization of the heart that follow such an increase in the amount of tissue.2,3 The specific genes which influence the maladaptive process of ventricular hypertrophy have not yet been totally elucidated; however, p53, a tumor suppressor encoded by TP53, has been implicated in some studies as the main regulator of the cardiac transcriptome in both cardiac homeostasis and heart failure.4 These findings suggest a potential relationship between p53 and maladaptive hypertrophy post-pressure overload. Methods. p53-KO experimental group mice were subject to either aortic banding5 (method 1) or transaortic constriction6 (method 2) techniques to induce a pressure-overloaded state. Echocardiography was performed pre- and post-procedure to analyze systolic and diastolic function of hearts. Both experimental and control group mice were sacrificed either 2 or 4 weeks post-procedure; hearts were then harvested, fixed, and stained with hematoxylin/eosin and Masson’s trichrome for immunohistochemical analysis. RT-qPCR and Western Blot were employed for analysis of genomic expression in harvested hearts. Results. Deletion of p53 in older, healthy mice hearts triggered spontaneous cardiac hypertrophy4; however, in injured post-pressure overload murine p53 KO hearts, remodeling processes were attenuated as measured by reduced LV wall thickness and reduced expression of hypertrophic biomarkers like ANP, BNP, and β-MHC.5 Deletion of p53 in post-pressure overload murine hearts also resulted in reduced systolic dysfunction as measured by fractional shortening and left ventricular end systolic diameter.6 p53-deficient mice hearts also expressed increased HIF1α/VEGF signaling in the murine heart as measured by Western blot; these pathways are fundamental to angiogenesis and vascularization in a growth environment.5 Conclusions. Deficiency of p53 in murine hearts was determined to reduce maladaptive hypertrophic remodeling processes and significantly increase expression of angiogenic growth factors like VEGF and HIF1α. Given that p53 knockout has been shown to limit the occurrence of two crucial steps in the pathogenesis of heart disease, p53 should be considered a potential therapeutic target worth studying further for use in patients at risk for heart failure due to chronically pressure-overloaded disease states.
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