Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension.

Abstract

INTRODUCTION:

An excess of angiotensin II (Ang II) causes hypertension and vascular injury. Activation of mitogen-activated protein kinase p38 (p38-MAPK) plays a substantial role in Ang II-dependent organ damage. Recently, we showed that p38-MAPK activation regulates the pressor response to Ang II. This study evaluates the effect of chronic p38-MAPK inhibition in Ang II-dependent hypertension.

MATERIALS AND METHODS:

C57Bl/6J mice were infused with Ang II for 14 days and either treated with the p38-MAPK inhibitor BIRB796 (50 mg/kg/day) or the vehicle as the control. We assessed vascular function in the aorta and isolated perfused kidneys.

RESULTS:

Chronic p38-MAPK inhibition did not alter blood pressure at the baseline, but attenuated Ang II-induced hypertension significantly (baseline: 122 ± 2 versus 119 ± 4 mmHg; Ang II: 173 ± 3 versus 155 ± 3 mmHg; p < 0.001). In addition, BIRB796 treatment improved vascular remodeling by reducing the aortic media-to-lumen ratio and decreasing the expression of the membrane metalloproteinases (MMP) MMP-1 and MMP-9. Moreover, renal vascular dysfunction induced by chronic Ang II infusion was significantly ameliorated in the BIRP796-treated mice. Acute p38-MAPK inhibition also improved vascular function in the aorta and kidneys of Ang II-treated mice, highlighting the important role of p38-MAPK activation in the pathogenesis of vascular dysfunction.

CONCLUSIONS:

Our findings indicated there is an important role for p38-MAPK in regulating blood pressure and vascular injury, and highlighted its potential as a pharmaceutical target.

• Authors: S A Potthoff, S Stamer, K Grave, E Königshausen, S H Sivritas, M Thieme, Y Mori, M Woznowski, L C Rump, J Stegbauer
• Journal: Journal of the renin-angiotensin-aldosterone system : JRAAS (J Renin Angiotensin Aldosterone Syst) Vol. 17 Issue 3 (Jul 2016) ISSN: 1752-8976 [Electronic] England
• PMID: 27407119 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2016.

Chemical References

• Protein Kinase Inhibitors
• Angiotensin II
• S-Nitrosoglutathione
• p38 Mitogen-Activated Protein Kinases

Topics

• Angiotensin II
• Animals
• Aorta (drug effects, physiopathology)
• Blood Pressure (drug effects)
• Hypertension (enzymology, physiopathology)
• Kidney (drug effects, physiopathology)
• Mice, Inbred C57BL
• Perfusion
• Protein Kinase Inhibitors (pharmacology)
• S-Nitrosoglutathione (pharmacology)
• Systole (drug effects)
• Vascular Remodeling (drug effects)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors)