Abstract 15: Loss of Tumor Suppressor Protein p53 is linked to High Blood Pressure

Abstract

Emerging evidence suggests that chronic inflammation plays a critical role in the development of hypertension. The tumor suppressor protein p53 is a key regulator of inflammation pathways. We therefore hypothesized that loss of p53 activity increases blood pressure (BP) by unleashing inflammatory responses. To test this hypothesis 8-week old p53-null (p53 -/- ) and wild-type mice (N=6, each group) were implanted with telemetry transmitters into the carotid arteries. After a 2 week recovery period post-surgery, BP was recorded continuously for 72 hours. Autonomic functions were assessed using IP administration of Methylatropine (dose 1mg/kg), propranolol (6mg/kg), and ganglionic blocker chlorisondamine (5mg/kg). Daytime BP (MAP: 109.4±2.3 vs. 95.5±1.1mmHg) is significantly higher in p53 -/- mice compared to wild-type mice (P< 0.05). Heart rate (HR) response to propranolol was significantly greater in p53 -/- mice (delta HR: 89.9±13.2bpm) compared to wild-type mice (delta HR: 45.9±7.8bpm, P<0.05) indicating that p53 -/- mice have greater cardiac sympathetic tone. Furthermore, the BP response to chlorisondamine is greater in p53 -/- mice (delta BP: 43.3±2.6mmHg) compared to wild-type mice (delta BP: 20.7±2.0mmHg, P<0.01), suggesting that p53 -/- mice harbor higher vasomotor sympathetic tone. To gain insight into the involvement of neural components in elevating BP in the null mice, transcriptome analysis was done on hypothalamic genes. Gene Ontological Biological Process (GO_BP) classification of differentially regulated genes revealed genes involved in immune response and inflammation. These includes chemokine ligand 17 (1.8 fold increase, P<0.05), tumor necrosis factor receptor 1B (2.2 fold increase, P<0.05), and nerve growth factor receptor (TNFR superfamily, member 16, Ngfr) (1.5 fold increase, P<0.05). In summary, p53 deletion increases BP, HR, and cardiac and vasomotor sympathetic activity and is associated with increases in genes involved in immune response and inflammatory pathways in the hypothalamus of the brain. These data provide a hitherto unrecognized link between tumor suppression, inflammation and blood pressure.