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Editing of the myosin phosphatase regulatory subunit suppresses angiotensin II induced hypertension via sensitization to nitric oxide mediated vasodilation

  • Integrative physiology
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Abstract

Alternative splicing of exon 24 (E24) of the myosin phosphatase regulatory subunit (Mypt1) tunes smooth muscle sensitivity to NO/cGMP-mediated vasorelaxation and thereby controls blood pressure (BP) in otherwise normal mice. This occurs via the toggling in or out of a C-terminal leucine zipper (LZ) motif required for hetero-dimerization with and activation by cGMP-dependent protein kinase cGK1α. Here we tested the hypothesis that editing (deletion) of E24, by shifting to the LZ positive isoform of Mypt1, would suppress the hypertensive response to angiotensin II (AngII). To test this, mice underwent tamoxifen-inducible and smooth muscle-specific deletion of E24 (E24 cKO) at age 6 weeks followed by a chronic slow-pressor dose of AngII (400 ng/kg/min) plus additional stressors. E24 cKO suppressed the hypertensive response to AngII alone or with the addition of a high salt diet. This effect was not a function of altered salt balance as there were no differences in intake or renal excretion of sodium. This effect was NO dependent as L-NAME in the drinking water caused an exaggerated hypertensive response in the E24cKO mice. E24cKO mouse mesenteric arteries were more sensitive to DEA/NO-induced vasorelaxation and less responsive to AngII- and α-adrenergic-induced vasoconstriction at baseline. Only the latter two effects were still present after 2 weeks of chronic AngII treatment. We conclude that editing of Mypt1 E24, by shifting the expression of naturally occurring isoforms and sensitizing to NO-mediated vasodilation, could be a novel approach to the treatment of human hypertension.

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Acknowledgments

We thank Owen Woodward for use of the Easylyte PLUS electrolyte analyzer, Paul A. Welling for the use of the metabolic cages, and the University of Maryland Cardiovascular Physiology Phenotyping Core for help with mouse telemetry and echocardiography.

Funding

This work was supported by NIH R01 HL142971-A1 and VA MERIT award BX004443 to SAF and NIH supplemental award 3R01HL130750-03S1 to JU.

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Authors and Affiliations

  1. Department of Medicine (Cardiology) and Physiology and Biophysics, University of Maryland-Baltimore, Baltimore, MD, 21201, USA

    Myo Htet, Jeanine A. Ursitti, Ling Chen & Steven A. Fisher

  2. Department of Physiology , University of Maryland- Baltimore , MD, 21201, Baltimore, USA

    Ling Chen

  3. Department of Medicine, Division of Cardiovascular Medicine, University of Maryland-Baltimore, Baltimore, MD, 21201, USA

    Steven A. Fisher

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  1. Myo Htet
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Htet, M., Ursitti, J.A., Chen, L. et al. Editing of the myosin phosphatase regulatory subunit suppresses angiotensin II induced hypertension via sensitization to nitric oxide mediated vasodilation. Pflugers Arch - Eur J Physiol 473, 611–622 (2021). https://doi.org/10.1007/s00424-020-02488-w

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