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Angiotensin III induces p38 Mitogen-activated protein kinase leading to proliferation of vascular smooth muscle cells

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Abstract

Background

Mitogen-activated protein kinases (MAPKs) are essential molecular transducers of extracellular stimuli into intracellular responses. MAPKs are crucial in mediating actions of the renin–angiotensin–aldosterone system (RAAS), in particular, functions mediated by Angiotensin (Ang) II, the main biological peptide produced by this system. We have shown that another biologically active heptapeptide Ang III also induces MAPKs in the central nervous system. The ability of Ang III to induce MAPKs in the periphery is unknown and was the focus of this study.

Methods

We determined whether Ang III induced p38 MAPK in vascular smooth cells (VSMCs) isolated from Wistar and spontaneously hypertensive rats (SHRs) and compared these actions to those of Ang II. Further, the role of this MAPK in Ang III-mediated VSMC proliferation was also determined.

Results

Both Ang peptides similarly induced p38 MAPK phosphorylation in VSMCs of Wistar VSMCs in a concentration- and time-dependent manner. SHR VSMCs were less sensitive to Ang III, which caused less of an effect on p38 MAPK phosphorylation in these cells. The Ang III effect was specific and occurred by activation of the Ang type 1 (AT1) receptor. The p38 MAPK pathway was also involved in Ang III-induced VSMC growth, as measured by DNA synthesis.

Conclusions

These findings suggest that the p38 MAPK signaling pathway is an important cascade in regulating the actions of Ang III in VSMCs. Most importantly, dysregulation of Ang III actions in these cells are apparent and may contribute to pathological conditions associated with dysfunctions in VSMCS.

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Acknowledgements

The authors are grateful for the technical assistance of Mr. Michael Dressler.

Funding

This work was supported by a President’s Faculty Research and Development Grant and a Health Professions Division Grant from Nova Southeastern University. The authors extend their sincere appreciation to the Deanship of Scientific Research and the Research Center, College of Pharmacy, King Saud University for funding the research project.

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Author notes

  1. Ahmed Z. Alanazi

    Present address: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA

    Ahmed Z. Alanazi & Michelle A. Clark

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  1. Ahmed Z. Alanazi
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  2. Michelle A. Clark
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Correspondence to Michelle A. Clark.

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Alanazi, A.Z., Clark, M.A. Angiotensin III induces p38 Mitogen-activated protein kinase leading to proliferation of vascular smooth muscle cells. Pharmacol. Rep 72, 246–253 (2020). https://doi.org/10.1007/s43440-019-00035-8

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  • DOI: https://doi.org/10.1007/s43440-019-00035-8

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