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<p>Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and predominantly affects older individuals, yet effective treatments remain limited. The molecular mechanisms linking cardiac aging to HFpEF are not fully understood. Here we show that the transcriptional regulator <i>Sub1</i> is upregulated in aged hearts and in mouse models of HFpEF. Cardiac overexpression of Sub1 shortens lifespan, exacerbates diastolic dysfunction, and accelerates cardiac aging, whereas Sub1 knockdown delays cardiac aging and alleviates HFpEF features, even when initiated in aged mice. Mechanistically, Sub1 interacted with TAF9b and AROS to stabilize p53 by regulating its ubiquitination and acetylation, thereby promoting cardiomyocyte senescence. Furthermore, disrupting the Sub1–p53 interaction attenuates cardiomyocyte senescence in vitro. These findings identify <i>Sub1</i> as a contributor to aging-associated HFpEF and provide insight into the molecular links between cardiac aging and disease progression.</p>

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Sub1 contributes to heart failure with preserved ejection fraction driven by aging in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月6日

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  • Di Zhao,
  • Ling Lin,
  • Yufei Zhou,
  • Jiaying Wu,
  • Ran Xu,
  • Linnan Li,
  • Xiaoxue Zhang,
  • Hong Lin,
  • Jienan Wang,
  • Kunming Dai,
  • Zhiwen Ding,
  • Pan Gao,
  • Jian Wu,
  • Yunzeng Zou

摘要

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and predominantly affects older individuals, yet effective treatments remain limited. The molecular mechanisms linking cardiac aging to HFpEF are not fully understood. Here we show that the transcriptional regulator Sub1 is upregulated in aged hearts and in mouse models of HFpEF. Cardiac overexpression of Sub1 shortens lifespan, exacerbates diastolic dysfunction, and accelerates cardiac aging, whereas Sub1 knockdown delays cardiac aging and alleviates HFpEF features, even when initiated in aged mice. Mechanistically, Sub1 interacted with TAF9b and AROS to stabilize p53 by regulating its ubiquitination and acetylation, thereby promoting cardiomyocyte senescence. Furthermore, disrupting the Sub1–p53 interaction attenuates cardiomyocyte senescence in vitro. These findings identify Sub1 as a contributor to aging-associated HFpEF and provide insight into the molecular links between cardiac aging and disease progression.