Long noncoding RNA SALTe1, microvascular ageing, and cardiac dysfunction
10 affiliations
- 1Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
- 2Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
- 3Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA
- 4Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA
- 5Stanley and Judith Frankel Institute for Heart and Brain Health, University of Michigan Medical Center, North Campus Research Complex, 2800 Plymouth Road, NCRC Building 25, Ann Arbor, MI 48109-2800, USA
- 6Chair for Gender Medicine, University of Zurich, Zurich 8006, Switzerland
- 7Department of Cardiology, University Hospital Zurich, Zurich 8091, Switzerland
- 8German Center for Heart and Cardiovascular Research (DZHK), Heidelberg, Germany
- 9Department of Cardiology, University Hospital Heidelberg, Heidelberg 69120, Germany
- 10Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Abstract
Background and Aims: Ageing is accompanied by progressive microvascular dysfunction, a key determinant of organ performance and longevity. The molecular drivers of this process remain incompletely defined, and the mechanisms by which exercise counters vascular ageing are unclear. This study investigated whether exercise-regulated long noncoding RNAs (lncRNAs) contribute to microvascular ageing and age-related cardiac dysfunction.
Methods: RNA sequencing was performed in naturally aged mice with and without voluntary exercise. Functional studies of candidate lncRNAs were conducted using AAV-mediated overexpression, antisense oligonucleotides, and CRISPR-based knockdown, both in vivo and in endothelial cells (ECs).
Results: A novel set of lncRNAs altered in hearts from exercised aged mice was identified and termed Senescence Associated LncRNA Transcripts in Exercise (SALTes). Among these, SALTe1 is evolutionarily conserved and enriched in ECs. SALTe1 expression is elevated in hearts from aged mice and in patients with various types of heart failure but suppressed by exercise. In 20-month-old mice, SALTe1 inhibition, via antisense GapmeRs or EC-specific deletion, attenuated endothelial senescence, restored microvascular perfusion, and improved diastolic function. Mechanistic studies showed that SALTe1 acts, at least in part, through upregulation of PARP9.
Conclusions: These findings establish SALTe1 as a pivotal regulator of endothelial senescence as well as microvascular and cardiac dysfunction in ageing. Targeted inhibition of SALTe1 recapitulates the vasculoprotective effects of exercise, highlighting a tractable antisense-based therapeutic strategy for combating age-related cardiac decline.
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BibTeX
@article{li2026long,
title = {{Long noncoding RNA SALTe1, microvascular ageing, and cardiac dysfunction}},
author = {Haobo Li and Xiao Xiao and Yirong Zhou and Yajing Zhang and Jiayi Kang and Zixun Yuan and Jiaqi He and Justin Guerra and Carolin Lerchenmüller and Kenneth B. Margulies and Aaron D. Aguirre and Jason D. Roh and Anthony Rosenzweig},
journal = {European heart journal},
year = {2026},
month = may,
doi = {10.1093/eurheartj/ehag356},
url = {https://doi.org/10.1093/eurheartj/ehag356},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Long noncoding RNA SALTe1, microvascular ageing, and cardiac dysfunction
AU - Haobo Li
AU - Xiao Xiao
AU - Yirong Zhou
AU - Yajing Zhang
AU - Jiayi Kang
AU - Zixun Yuan
AU - Jiaqi He
AU - Justin Guerra
AU - Carolin Lerchenmüller
AU - Kenneth B. Margulies
AU - Aaron D. Aguirre
AU - Jason D. Roh
AU - Anthony Rosenzweig
PY - 2026
DA - 2026/05/19
JO - European heart journal
DO - 10.1093/eurheartj/ehag356
UR - https://doi.org/10.1093/eurheartj/ehag356
AB - Background and Aims: Ageing is accompanied by progressive microvascular dysfunction, a key determinant of organ performance and longevity. The molecular drivers of this process remain incompletely defined, and the mechanisms by which exercise counters vascular ageing are unclear. This study investigated whether exercise-regulated long noncoding RNAs (lncRNAs) contribute to microvascular ageing and age-related cardiac dysfunction. Methods: RNA sequencing was performed in naturally aged mice with and without voluntary exercise. Functional studies of candidate lncRNAs were conducted using AAV-mediated overexpression, antisense oligonucleotides, and CRISPR-based knockdown, both in vivo and in endothelial cells (ECs). Results: A novel set of lncRNAs altered in hearts from exercised aged mice was identified and termed Senescence Associated LncRNA Transcripts in Exercise (SALTes). Among these, SALTe1 is evolutionarily conserved and enriched in ECs. SALTe1 expression is elevated in hearts from aged mice and in patients with various types of heart failure but suppressed by exercise. In 20-month-old mice, SALTe1 inhibition, via antisense GapmeRs or EC-specific deletion, attenuated endothelial senescence, restored microvascular perfusion, and improved diastolic function. Mechanistic studies showed that SALTe1 acts, at least in part, through upregulation of PARP9. Conclusions: These findings establish SALTe1 as a pivotal regulator of endothelial senescence as well as microvascular and cardiac dysfunction in ageing. Targeted inhibition of SALTe1 recapitulates the vasculoprotective effects of exercise, highlighting a tractable antisense-based therapeutic strategy for combating age-related cardiac decline.
SN - 0195-668X
SN - 1522-9645
ER -