2. Academic Validation
  3. Increased β-adrenergic stimulation augments vascular smooth muscle cell calcification via PKA/CREB signalling

Increased β-adrenergic stimulation augments vascular smooth muscle cell calcification via PKA/CREB signalling

  • Pflugers Arch. 2021 Dec;473(12):1899-1910. doi: 10.1007/s00424-021-02621-3.
Barbara Moser 1,  Florian Poetsch 1,  Misael Estepa 2,  Trang T D Luong 1,  Burkert Pieske 2 3 4 5,  Florian Lang 6,  Ioana Alesutan 7,  Jakob Voelkl 1 3 8
Affiliations

Affiliations

  • 1 Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Altenberger Strasse 69, 4040, Linz, Austria.
  • 2 Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
  • 3 DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
  • 4 Department of Internal Medicine and Cardiology, German Heart Center Berlin (DHZB), Berlin, Germany.
  • 5 Berlin Institute of Health (BIH), Berlin, Germany.
  • 6 Department of Physiology I, Eberhard-Karls University Tübingen, Tübingen, Germany.
  • 7 Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Altenberger Strasse 69, 4040, Linz, Austria. ioana.alesutan@jku.at.
  • 8 Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.
PMID: 34564739 DOI: 10.1007/s00424-021-02621-3
Abstract

In chronic kidney disease (CKD), hyperphosphatemia promotes medial vascular calcification, a process augmented by osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). VSMC function is regulated by sympathetic innervation, and these cells express α- and β-adrenergic receptors. The present study explored the effects of β2-adrenergic stimulation by isoproterenol on VSMC calcification. Experiments were performed in primary human aortic VSMCs treated with isoproterenol during control or high phosphate conditions. As a result, isoproterenol dose dependently up-regulated the expression of osteogenic markers core-binding factor α-1 (CBFA1) and tissue-nonspecific Alkaline Phosphatase (ALPL) in VSMCs. Furthermore, prolonged isoproterenol exposure augmented phosphate-induced calcification of VSMCs. Isoproterenol increased the activation of PKA and CREB, while knockdown of the PKA catalytic subunit α (PRKACA) or of CREB1 genes was able to suppress the pro-calcific effects of isoproterenol in VSMCs. β2-adrenergic receptor silencing or inhibition with the selective antagonist ICI 118,551 blocked isoproterenol-induced osteogenic signalling in VSMCs. The present observations imply a pro-calcific effect of β2-adrenergic overstimulation in VSMCs, which is mediated, at least partly, by PKA/CREB signalling. These observations may support a link between sympathetic overactivity in CKD and vascular calcification.

Keywords

CREB; Isoproterenol; Phosphate; Protein kinase A; Sympathetic overactivity; Vascular calcification; Vascular smooth muscle cells; β-adrenergic receptor.

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