Inhibiting airway smooth muscle contraction using pitavastatin: A role for the mevalonate pathway in regulating cytoskeletal proteins

Robin A. Lu, Amir A. Zeki, Sumati Ram-Mohan, Nhan Nguyen, Yan Bai, Kenneth Chmiel, Stevan Pecic, Xingbin Ai, Ramaswamy Krishnan, Chandra C. Ghosh

    Research output: Contribution to journalArticle

    Abstract

    Despite maximal use of currently available therapies, a significant number of asthma patients continue to experience severe, and sometimes life-threatening bronchoconstriction. To fill this therapeutic gap, we examined a potential role for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor, pitavastatin. Using human airway smooth muscle (ASM) cells and murine precision-cut lung slices, we discovered that pitavastatin significantly inhibited basal-, histamine-, and methacholine (MCh)-induced ASM contraction. This occurred via reduction of myosin light chain 2 (MLC2) phosphorylation, and F-actin stress fiber density and distribution, in a mevalonate (MA)- and geranylgeranyl pyrophosphate (GGPP)-dependent manner. Pitavastatin also potentiated the ASM relaxing effect of a simulated deep breath, a beneficial effect that is notably absent with the b2-agonist, isoproterenol. Finally, pitavastatin attenuated ASM pro-inflammatory cytokine production in a GGPP-dependent manner. By targeting all three hallmark features of ASM dysfunction in asthma—contraction, failure to adequately relax in response to a deep breath, and inflammation—pitavastatin may represent a unique asthma therapeutic.

    Original languageEnglish (US)
    Article number469
    JournalFrontiers in Pharmacology
    Volume11
    DOIs
    StatePublished - May 2020

    Keywords

    • Asthma
    • Bronchodilation
    • Inflammation
    • Mechanics
    • Mechanopharmacology
    • Mevalonate
    • Statin
    • Stretch

    ASJC Scopus subject areas

    • Pharmacology
    • Pharmacology (medical)

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