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.
Authors
- Ginger Rakestraw
- Tohru Minamino (ORCID: https://orcid.org/0000-0003-1627-6151)
- Yuya Kinoshita (ORCID: https://orcid.org/0000-0001-8695-2501)
- Kimitoshi Nakamura (ORCID: https://orcid.org/0000-0001-6659-4145)
- Leonard P. Adam (ORCID: https://orcid.org/0000-0001-7387-7071)
- Daisuke Torigoe (ORCID: https://orcid.org/0009-0007-9924-4994)
- Tsuyoshi Kadomatsu (ORCID: https://orcid.org/0000-0003-3327-6954)
- Hiromasa Otake (ORCID: https://orcid.org/0000-0001-9953-0551)
- Yuichi Oike (ORCID: https://orcid.org/0000-0003-3245-5395)
- Seitaro Nomura (ORCID: https://orcid.org/0000-0002-2957-2016)
- Yusuke Okadome (ORCID: https://orcid.org/0009-0003-1330-7546)
- Kazutaka Ikeda (ORCID: https://orcid.org/0000-0001-9247-4593)
- Koichi Node (ORCID: https://orcid.org/0000-0002-2534-0939)
- 倉林 篤史
- Takanori Yamaguchi (ORCID: https://orcid.org/0000-0002-0613-8591)
- Haruki Horiguchi (ORCID: https://orcid.org/0000-0001-9344-8362)
- Aaron P. Yamniuk
- Goro Yoshioka (ORCID: https://orcid.org/0000-0002-3735-9258)
- Tomohiko Wakayama (ORCID: https://orcid.org/0000-0002-8795-7950)
- Manami Katoh (ORCID: https://orcid.org/0000-0001-5634-9170)
- Keishi Miyata (ORCID: https://orcid.org/0000-0003-0336-1859)
- Michio Sato (ORCID: https://orcid.org/0000-0001-9339-1642)
- Ryoko Kusaba
- Wataru Fujimoto
- Peiwen Xu
- Burçe Ergel Gurbuzbalaban
- Gordon Teg Pipes
- Yuya Matsue
Institutions
- Saga University (JP)
- Juntendo University (JP)
- Bristol-Myers Squibb (United States) (US)
- Hyogo Prefectural Awaji Medical Center (JP)
- National Cerebral and Cardiovascular Center (JP)
- Kazusa DNA Research Institute (JP)
- Kumamoto Industrial Research Institute (JP)
- Kobe University (JP)
- The University of Tokyo (JP)
- Kumamoto University (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-16
- DOI
- https://doi.org/10.1038/s41467-026-78375-2
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
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