Hypertensive stress rewires macrophage signaling in heart failure with preserved ejection fraction independent of obesity
Year: 2026
Type: article
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.
Source: Nature Communications
Authors: Yuya Kinoshita, Michio Sato, Tsuyoshi Kadomatsu, Manami Katoh, Kazutaka Ikeda, Goro Yoshioka, Yuya Matsue, Wataru Fujimoto, Atsushi Kurabayashi, Yusuke Okadome, Daisuke Torigoe, Tomohiko Wakayama, Haruki Horiguchi, Ryoko Kusaba, Xu Peiwen, Burçe Ergel Gurbuzbalaban, Ginger Rakestraw, Aaron Yamniuk, Gordon Teg Pipes, Leonard Adam, Keishi Miyata, Takanori Yamaguchi, Hiromasa Otake, Tohru Minamino, Seitaro Nomura, Kimitoshi Nakamura, Koichi Node, Yuichi Oike
Institutions: Kumamoto University, Saga University, Kumamoto Industrial Research Institute, National Cerebral and Cardiovascular Center, The University of Tokyo, Kazusa DNA Research Institute, Juntendo University, Hyogo Prefectural Awaji Medical Center, Bristol-Myers Squibb (United States), Kobe University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Bristol-Myers Squibb, Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, Japanese Circulation Society, Mochida Memorial Foundation for Medical and Pharmaceutical Research, SENSHIN Medical Research Foundation, NOVARTIS Foundation (Japan) for the Promotion of Science, Japan Heart Foundation, Core Research for Evolutional Science and Technology
OpenAlex ID: W7222722835
FWCI:
Cites:
Cited by:
Related to: