Hypertensive stress rewires macrophage signaling in heart failure with preserved ejection fraction independent of obesity
Abstract
Heart failure with preserved ejection fraction (HFpEF) remains a major unmet clinical challenge. Although obesity is common in many HFpEF cohorts from Europe and North America, three Japanese HFpEF cohorts identified hypertension and sympathetic overactivation, rather than obesity, as dominant features. To model these features, we established an HFpEF mouse model in which sympathetic activation induces hypertensive heart disease, while endothelial dysfunction acts as a second hit driving progression to HFpEF. Hypertensive stress rewires cardiac macrophage-derived intercellular signaling, impairing macrophage-to-cardiomyocyte BMP signaling and fatty acid oxidation while enhancing macrophage-to-fibroblast PDGF signaling, thereby promoting metabolic remodeling, inflammation, and fibrosis. ANGPTL2 inhibition preserves macrophage intercellular communication and prevents HFpEF development. These findings identify cardiac macrophage signaling rewiring as a central mechanism linking hypertensive stress to metabolic remodeling and inflammation, revealing a pathogenic pathway for HFpEF in the absence of obesity that is distinct from HFpEF associated with obesity.
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BibTeX
@article{kinoshita2026hypertensive,
title = {{Hypertensive stress rewires macrophage signaling in heart failure with preserved ejection fraction independent of obesity}},
author = {Yuya Kinoshita and Michio Sato and Tsuyoshi Kadomatsu and Manami Katoh and Kazutaka Ikeda and Goro Yoshioka and Yuya Matsue and Wataru Fujimoto and Atsushi Kurabayashi and Yusuke Okadome and Daisuke Torigoe and Tomohiko Wakayama and Haruki Horiguchi and Ryoko Kusaba and Xu Peiwen and Burçe Ergel Gurbuzbalaban and Ginger Rakestraw and Aaron Yamniuk and Gordon Teg Pipes and Leonard Adam and Keishi Miyata and Takanori Yamaguchi and Hiromasa Otake and Tohru Minamino and Seitaro Nomura and Kimitoshi Nakamura and Koichi Node and Yuichi Oike},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78375-2},
url = {https://www.nature.com/articles/s41467-026-78375-2},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hypertensive stress rewires macrophage signaling in heart failure with preserved ejection fraction independent of obesity
AU - Yuya Kinoshita
AU - Michio Sato
AU - Tsuyoshi Kadomatsu
AU - Manami Katoh
AU - Kazutaka Ikeda
AU - Goro Yoshioka
AU - Yuya Matsue
AU - Wataru Fujimoto
AU - Atsushi Kurabayashi
AU - Yusuke Okadome
AU - Daisuke Torigoe
AU - Tomohiko Wakayama
AU - Haruki Horiguchi
AU - Ryoko Kusaba
AU - Xu Peiwen
AU - Burçe Ergel Gurbuzbalaban
AU - Ginger Rakestraw
AU - Aaron Yamniuk
AU - Gordon Teg Pipes
AU - Leonard Adam
AU - Keishi Miyata
AU - Takanori Yamaguchi
AU - Hiromasa Otake
AU - Tohru Minamino
AU - Seitaro Nomura
AU - Kimitoshi Nakamura
AU - Koichi Node
AU - Yuichi Oike
PY - 2026
DA - 2026/10/16
JO - Nature Communications
DO - 10.1038/s41467-026-78375-2
UR - https://www.nature.com/articles/s41467-026-78375-2
AB - Heart failure with preserved ejection fraction (HFpEF) remains a major unmet clinical challenge. Although obesity is common in many HFpEF cohorts from Europe and North America, three Japanese HFpEF cohorts identified hypertension and sympathetic overactivation, rather than obesity, as dominant features. To model these features, we established an HFpEF mouse model in which sympathetic activation induces hypertensive heart disease, while endothelial dysfunction acts as a second hit driving progression to HFpEF. Hypertensive stress rewires cardiac macrophage-derived intercellular signaling, impairing macrophage-to-cardiomyocyte BMP signaling and fatty acid oxidation while enhancing macrophage-to-fibroblast PDGF signaling, thereby promoting metabolic remodeling, inflammation, and fibrosis. ANGPTL2 inhibition preserves macrophage intercellular communication and prevents HFpEF development. These findings identify cardiac macrophage signaling rewiring as a central mechanism linking hypertensive stress to metabolic remodeling and inflammation, revealing a pathogenic pathway for HFpEF in the absence of obesity that is distinct from HFpEF associated with obesity.
SN - 2041-1723
ER -