Abstract 389: Angiotensin-(1-7) Modulates Renal Vascular Resistance Through Inhibition of Mitogen- Activated Protein Kinase (MAPK) P38 in Apolipoproteine (apoE) Deficient Mice
ApoE-KO mice are characterized by endothelial dysfunction and increased vasoconstrictor response. Previously, we have shown that chronic Ang-(1-7) treatment ameliorates endothelial dysfunction in apoE-KO. However, the impact of Ang-(1-7) on vasoconstrictor response to AngII is unknown. To examine the role of Ang-(1-7) in vascular resistance in atherosclerosis, apoE-KO and wild type (WT) mice fed on western diet were treated via osmotic minipumps either with Ang-(1-7) (82μg/kg/hr) or saline for 6 weeks. Vascular resistance was tested in isolated perfused kidneys. AngII induced renal pressor response was significantly increased in apoE-KO compared to WT mice. Remarkably, chronic Ang-(1-7) treatment attenuated AngII induced pressor response in apoE-KO mice. Accordingly, in apoE-KO, phospho-MLC20, a marker of enhanced contractility was increased in preglomerular vessels compared to WT and reduced after Ang-(1-7) treatment. To examine the underlying cause, we measured reactive oxygen species (ROS) production and changes in NADP(H) expression levels. In apoE-KO mice, p47phox was increased (1.5-fold; P<0.05) compared to WT and reduced after chronic Ang-(1-7) treatment. Concordantly, urinary isoprostane-8 excretion and H2O2 generation were significantly decreased in Ang-(1-7) treated apoE-KO mice. ROS is known to activate the MAPK p38. Moreover, p38 has shown to modulate pressor response. To test the role of p38 in our model, we measured p38 activity and renal pressor response to AngII in the presence of SB203580, a specific p38 inhibitor. Thus, in preglomerular vessels of apoE-KO, the phospho-p38 / p38 ratio was increased compared to WT. Chronic Ang-(1-7) treatment restored this ratio almost to WT levels (2.8±0.5 vs. 1.0±0.1 vs. 1.3±0.2 P<0.05). Administration of SB203580 (5μmol/L) reduced renal pressor response to AngII in apoE-KO but not in Ang-(1-7) treated mice. Hence, chronic inhibition of p38 with BIRB796 (30mg/kg) attenuated the increased pressor response to AngII in apoE-KO mice. In summary, p38 plays a crucial role in regulating renal vascular resistance in apoE-KO mice. Moreover, Ang-(1-7) attenuates pressor response to AngII by reducing p38 activity. Thus, this study revealed a new pathway how Ang-(1-7) modulates vascular function.
- © 2012 by American Heart Association, Inc.