Proteostatic Imbalance Drives the Pathogenesis and Age-Related Exacerbation of Heart Failure With Preserved Ejection Fraction
Heart failure with preserved ejection fraction (HFpEF) is a leading cause of hospitalization and mortality in older adults, yet the role of aging in its pathogenesis remains unclear. Old male mice subjected to chronic metabolic and hypertensive stress (2-hit) developed a more severe HFpEF phenotype compared with young counterparts. We identified that age-related disruptions in protein quality control (PQC) worsens proteostatic stress in HFpEF. Mammalian target of rapamycin complex 1 (mTORC1), a key regulator of PQC, is activated by both aging and 2-hit stress, and cardiac-specific mTORC1 inhibition protects against HFpEF. Our findings highlight the need to integrate aging into preclinical models of HFpEF and suggest targeting PQC as a therapeutic strategy.
Authors
- Agnieszka Borowik (ORCID: https://orcid.org/0000-0002-2208-460X)
- Judit Villén (ORCID: https://orcid.org/0000-0002-1005-1739)
- Ying Ann Chiao (ORCID: https://orcid.org/0000-0002-1256-4335)
- Sue C. Bodine (ORCID: https://orcid.org/0000-0002-5742-9145)
- Benjamin F. Miller (ORCID: https://orcid.org/0000-0003-3283-0685)
- Weronika Zarzycka (ORCID: https://orcid.org/0009-0009-5800-9925)
- Mario Leutert (ORCID: https://orcid.org/0000-0001-7921-4017)
- Leslie M. Baehr (ORCID: https://orcid.org/0000-0002-8778-3567)
- Ricard A. Rodríguez‐Mias (ORCID: https://orcid.org/0000-0001-7960-6387)
- Michael T Kinter (ORCID: https://orcid.org/0000-0001-7409-8918)
- Kamil Kobak (ORCID: https://orcid.org/0000-0003-1804-6333)
- Catherine King
- Frederick F. Peelor
Institutions
- University of Washington (US)
- Oklahoma Medical Research Foundation (US)
Publication Details
- Journal
- JACC Basic to Translational Science
- Published
- 2025-01-22
- DOI
- https://doi.org/10.1016/j.jacbts.2024.11.006
- Citations
- 6
- Primary Topic
- Cardiovascular Function and Risk Factors
- Type
- article
- Field-Weighted Citation Impact
- 8.33
Funders
- U.S. Department of Veterans Affairs
- American Heart Association
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institute on Aging
- National Institute of General Medical Sciences