Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension
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....
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publications
2016-07-01
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| Series: | Journal of the Renin-Angiotensin-Aldosterone System |
| Online Access: | https://doi.org/10.1177/1470320316653284 |
| _version_ | 1797281975620337664 |
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| author | SA Potthoff S Stamer K Grave E Königshausen SH Sivritas M Thieme Y Mori M Woznowski LC Rump J Stegbauer |
| author_facet | SA Potthoff S Stamer K Grave E Königshausen SH Sivritas M Thieme Y Mori M Woznowski LC Rump J Stegbauer |
| author_sort | SA Potthoff |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:05:14Z |
| format | Article |
| id | doaj.art-d1f4200bbe6947cabf40fcab74b2b53a |
| institution | Directory Open Access Journal |
| issn | 1752-8976 |
| language | English |
| last_indexed | 2024-03-07T17:05:14Z |
| publishDate | 2016-07-01 |
| publisher | SAGE Publications |
| record_format | Article |
| series | Journal of the Renin-Angiotensin-Aldosterone System |
| spelling | doaj.art-d1f4200bbe6947cabf40fcab74b2b53a2024-03-03T02:50:18ZengSAGE PublicationsJournal of the Renin-Angiotensin-Aldosterone System1752-89762016-07-011710.1177/1470320316653284Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertensionSA Potthoff0S Stamer1K Grave2E Königshausen3SH Sivritas4M Thieme5Y Mori6M Woznowski7LC Rump8J Stegbauer9Department of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Nuclear Medicine, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyDepartment of Nephrology, University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine University, Düsseldorf, GermanyIntroduction: 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.https://doi.org/10.1177/1470320316653284 |
| spellingShingle | SA Potthoff S Stamer K Grave E Königshausen SH Sivritas M Thieme Y Mori M Woznowski LC Rump J Stegbauer Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension Journal of the Renin-Angiotensin-Aldosterone System |
| title | Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension |
| title_full | Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension |
| title_fullStr | Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension |
| title_full_unstemmed | Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension |
| title_short | Chronic p38 mitogen-activated protein kinase inhibition improves vascular function and remodeling in angiotensin II-dependent hypertension |
| title_sort | chronic p38 mitogen activated protein kinase inhibition improves vascular function and remodeling in angiotensin ii dependent hypertension |
| url | https://doi.org/10.1177/1470320316653284 |
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