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Publications

Journal Article Ppublish 6 citations

PubMed: 40306856 DOI: 10.1016/j.jacbts.2024.11.006

Proteostatic Imbalance Drives the Pathogenesis and Age-Related Exacerbation of Heart Failure With Preserved Ejection Fraction.

JACC Basic Transl Sci 10(4):475-497

Authors: Kamil A Kobak, Weronika Zarzycka, Catherine J King, Agnieszka K Borowik, Frederick F Peelor, Leslie M Baehr, Mario Leutert, Ricard A Rodriguez-Mias, Judit Villén, Sue C Bodine, Michael T Kinter, Benjamin F Miller, Ying Ann Chiao

Affiliations

  • Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
  • Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
  • Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
  • Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA.
  • Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA; Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Abstract

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.

MeSH

Autophagy, Heart Failure, Heart, Aging, Stress, Physiological, Heart Failure, Diastolic, Mechanistic Target Of Rapamycin Complex 1

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