P4474The role of nr4a1 in angiotensin-ii model of pressure overload induced cardiac remodelling

Abstract

Abstract Introduction Adverse cardiac remodelling is a response of the heart to various stimuli and if left untreated can progress to heart failure. Nr4a1, an orphan nuclear receptor, has been shown to have conflicting contributions to adverse cardiac remodelling in several aetiologies, making its role in cardiac remodelling unclear. Purpose To investigate the contribution of Nr4a1 to adverse remodelling in a model that does not cause a pressor response, in order to gain a clearer understanding of the actions of Nr4a1 in the absence of alterations in hemodynamic load. Methods 8 week old Nr4a1−/− mice received an IP infusion of Ang-II via osmotic pump (1500ng/kg) for 3 or 7 days. IP administration does not cause increased blood pressure. Age-matched wild type (WT) C57B/6 mice served as controls. Left ventricular (LV) structure and function was assessed by echocardiography and pressure catheter. LV tissue was collected for molecular and histological analyses. Results Echocardiography identified a trend towards a thickening of the LV anterior wall in the Nr4a1−/−+Ang-II 7 days group, which was also reflected in the increase in LV/tibia ratio (Nr4a1−/−+Ang-II 5.7±0.67 mg/mm vs WT+Ang-II 4.64±0.5 mg/mm, p<0.0003; Nr4a1−/−+Ang-II 5.7±0.67 mg/mm vs Nr4a1−/−+Saline 4.7±0.6 mg/mm, p<0.0008). No hypertrophy was observed in the WT+Ang-II 7 days group reflective of no haemodynamic load. Our results also showed that cardiac fibrosis was decreased in Nr4a1−/−+Ang-II mice following 7 days of Ang-II. LV end diastolic pressure was elevated in WT+Ang-II mice compared to WT+Saline mice (5.8±6.0 mmHg vs 1.2±2.0 mmHg, p<0.05), but normalised in Nr4a1−/−+Ang-II (2.4±2.9 mmHg) reflective of the reduced fibrosis in the Nr4a1−/−+Ang-II mice. Inflammation is an underlying cause of fibrosis. There was a significant increase in macrophages at 3 days in both WT+Ang-II (46.38±44.14 cells/LV section vs WT+Saline: 5.4±3.82 cells/LV section)and Nr4a1−/−+Ang-II mice (224.4±44.83 cells/LV section vs Nr4a1−/−+Saline: 8.04±10.59 cells/LV section). Nr4a1−/−+Ang-II also had increased macrophages compared to WT+Ang-II group (p<0.0001). The increase in macrophages does not appear to be due to recruitment since the chemokine CCL2 was not increased in Nr4a1−/− mice with Ang-II. In addition, despite the dramatic increase in inflammatory cell number in the Nr4a−/−+Ang-II mice, there does not appear to be an increased active inflammatory response since LV IL-6 levels were not increased in this group. LV end diastolic pressure Conclusion Nr4a1 plays a role in regulating cardiac remodelling with its absence making the heart more prone to cardiac hypertrophy in response to stimulation, even in the absence of hemodynamic load. Interestingly though, this hypertrophic response occurs with reduced fibrosis and normal LV end diastolic pressure, which together would seem to indicate adaptive hypertrophy as opposed to pathological hypertrophy in the absence of Nr4a1. Acknowledgement/Funding George and Mary Thompson Fellowship