Inhibiting Airway Smooth Muscle Contraction Using Pitavastatin: A Role for the Mevalonate Pathway in Regulating Cytoskeletal Proteins

Overview

Journal Front Pharmacol

Date 2020 May 22

PMID 32435188

Authors

Robin A Lu

Amir A Zeki

Sumati Ram-Mohan

Nhan Nguyen

Yan Bai

Kenneth Chmiel

Stevan Pecic

Xingbin Ai

Ramaswamy Krishnan

Chandra C Ghosh

Affiliations

Soon will be listed here.

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 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 β2-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.

Citing Articles

Targeting cytoskeletal biomechanics to modulate airway smooth muscle contraction in asthma.

McCullough M, Joshi I, Pereira N, Fuentes N, Krishnan R, Druey K J Biol Chem. 2024; 301(1):108028.

PMID: 39615690 PMC: 11721269. DOI: 10.1016/j.jbc.2024.108028.

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