BEST3-Mediated MEKK2/3 Activation: A Novel Therapeutic Target in Aortopathies

Authors

Tatiana Zyrianova, University of California, Los AngelesFollow
Benjamin Lopez, University of California, Los Angeles
Kathlyn Zou, University of California, Los Angeles
Charles Gu, University of California, Los Angeles
Dayna Pham, University of California, Los Angeles
Sriharsha Talapaneni, University of California, Los Angeles
Christopher M. Waters, University of KentuckyFollow
Riccardo Olcese, University of California, Los Angeles
Andreas Schwingshackl, University of California, Los AngelesFollow

Abstract

Influenza-A virus (IAV) infects yearly an estimated one billion people worldwide, resulting in 300,000–650,000 deaths. Preventive vaccination programs and antiviral medications represent the mainstay of therapy, but with unacceptably high morbidity and mortality rates, new targeted therapeutic approaches are urgently needed. Since inflammatory processes are commonly associated with measurable changes in the cell membrane potential (Em), we investigated whether Em hyperpolarization via TREK-1 (K2P 2.1) K þ channel activation can protect against influenza-A virus (IAV)-induced pneumonia. We infected mice with IAV, which after 5 days caused 10–15% weight loss and a decrease in spontaneous activity, representing a clinically relevant infection. We then started a 3-day intratracheal treatment course with the novel TREK-1 activating compounds BL1249 or ML335. We confirmed TREK-1 activation with both compounds in untreated and IAV-infected primary human alveolar epithelial cells (HAECs) using high-throughput fluorescent imaging plate reader (FLIPR) assays. In mice, TREK-1 activation with BL1249 and ML335 counteracted IAV-induced histological lung injury and decrease in lung compliance and improved BAL fluid total protein levels, cell counts, and inflammatory IL-6, IP-10/CXCL-10, MIP-1a, and TNF-a levels. To determine whether these anti-inflammatory effects were mediated by activation of alveolar epithelial TREK-1 channels, we studied the effects of BL1249 and ML335 in IAV-infected HAEC, and found that TREK-1 activation decreased IAV-induced inflammatory IL-6, IP-10/CXCL10, and CCL-2 secretion. Dissection of TREK-1 downstream signaling pathways and construction of protein-protein interaction (PPI) networks revealed NF- κB1 and retinoic acid-inducible gene-1 (RIG-1) cascades as the most likely targets for TREK-1 protection. Therefore, TREK-1 activation may represent a novel therapeutic approach against IAV-induced lung injury.

Document Type

Editorial

Publication Date

1-2023

Notes/Citation Information

1040-0605/23 Copyright © 2023 the American Physiological Society.

Digital Object Identifier (DOI)

https://doi.org/10.1152/ajplung.00116.2022

Funding Information

This study was supported by the following grants: NIH HL118118-3 and HL146821 (to A. Schwingshackl); NIH HL131526 and HL151419 (to C. M. Waters); NIH HL134346 (to R. Olcese); and W81XWH-22-1-0040 (U.S. Department of Defense, to T. Zyrianova).

Repository Citation

Zyrianova, Tatiana; Lopez, Benjamin; Zou, Kathlyn; Gu, Charles; Pham, Dayna; Talapaneni, Sriharsha; Waters, Christopher M.; Olcese, Riccardo; and Schwingshackl, Andreas, "BEST3-Mediated MEKK2/3 Activation: A Novel Therapeutic Target in Aortopathies" (2023). Saha Cardiovascular Research Center Faculty Publications. 70.
https://uknowledge.uky.edu/cvrc_facpub/70