12,13-diHOME protects against the age-related decline in cardiovascular function via attenuation of CaMKII

Shinsuke Nirengi, Benjamin Buck, Devleena Das, Carmem Peres Valgas da Silva, Jazmin Calyeca, Lisa A. Baer, Hsiang-Ling Huang, Pablo Vidal, Revati S. Dewal, Kelsey M. Pinckard, Elisa Félix-Soriano, Diego Hernandez-Saavedra, Andrew Gerea, Kavya Dathathreya, Silvia Duarte-Sanmiguel, Ty A. Saldana, Harrison L. Hookfin, Matthew W. Gorr, Valerie Bussberg, Juan J. Aristizabal-Henao, Michael A. Kiebish, Roeland J. W. Middelbeek, Laurie J. Goodyear, Paul M. Coen, Krishna Chinthalapudi, Loren E. Wold, Ana L. Mora, Thomas J. Hund, Daniel Gallego-Perez and Kristin I. Stanford ()
Additional contact information
Shinsuke Nirengi: The Ohio State University Wexner Medical Center
Benjamin Buck: The Ohio State University Wexner Medical Center
Devleena Das: The Ohio State University Wexner Medical Center
Carmem Peres Valgas da Silva: The Ohio State University Wexner Medical Center
Jazmin Calyeca: The Ohio State University Wexner Medical Center
Lisa A. Baer: The Ohio State University Wexner Medical Center
Hsiang-Ling Huang: The Ohio State University Wexner Medical Center
Pablo Vidal: The Ohio State University Wexner Medical Center
Revati S. Dewal: The Ohio State University Wexner Medical Center
Kelsey M. Pinckard: The Ohio State University Wexner Medical Center
Elisa Félix-Soriano: The Ohio State University Wexner Medical Center
Diego Hernandez-Saavedra: The Ohio State University Wexner Medical Center
Andrew Gerea: The Ohio State University Wexner Medical Center
Kavya Dathathreya: The Ohio State University Wexner Medical Center
Silvia Duarte-Sanmiguel: The Ohio State University Wexner Medical Center
Ty A. Saldana: The Ohio State University Wexner Medical Center
Harrison L. Hookfin: The Ohio State University Wexner Medical Center
Matthew W. Gorr: The Ohio State University Wexner Medical Center
Valerie Bussberg: BGPBio
Juan J. Aristizabal-Henao: BGPBio
Michael A. Kiebish: BGPBio
Roeland J. W. Middelbeek: Harvard Medical School
Laurie J. Goodyear: Harvard Medical School
Paul M. Coen: AdventHealth
Krishna Chinthalapudi: The Ohio State University Wexner Medical Center
Loren E. Wold: The Ohio State University Wexner Medical Center
Ana L. Mora: The Ohio State University Wexner Medical Center
Thomas J. Hund: The Ohio State University Wexner Medical Center
Daniel Gallego-Perez: The Ohio State University Wexner Medical Center
Kristin I. Stanford: The Ohio State University Wexner Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis of human and rodent plasma signaling lipids reveals a decline in 12,13-diHOME levels with age. Transplantation of BAT or sustained upregulation of 12,13-diHOME effectively preserved cardiac function in aged male and female mice. Bulk RNA-Seq of hearts from aged mice reveals significant increases in pathways involved in ER stress and fibrosis which were partially attenuated by BAT transplantation or sustained upregulation of 12,13-diHOME. Mechanistically, in vivo and in vitro models demonstrate that 12,13-diHOME alleviated ER stress through CaMKII inhibition, particularly in males. These findings underscore 12,13-diHOME as a promising candidate for combating age-related cardiovascular dysfunction, offering insights into potential therapeutic strategies for addressing cardiovascular diseases in aging populations.

Date: 2025
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DOI: 10.1038/s41467-025-62474-7

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