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

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Aging
• Heart Failure Pathophysiology

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a prevalent condition, particularly in older adults, with limited effective treatments.
• The molecular underpinnings connecting cardiac aging to HFpEF remain incompletely elucidated.

Purpose of the Study:

• To investigate the role of the transcriptional regulator Sub1 in cardiac aging and HFpEF.
• To elucidate the molecular mechanisms by which Sub1 influences cardiomyocyte senescence and HFpEF progression.

Main Methods:

• Analysis of Sub1 expression in aged hearts and HFpEF mouse models.
• Investigating the effects of cardiac Sub1 overexpression and knockdown on lifespan, cardiac function, and aging markers in mice.
• Examining the interaction of Sub1 with TAF9b and AROS to regulate p53 stability.
• Assessing the impact of disrupting the Sub1-p53 interaction on cardiomyocyte senescence in vitro.

Main Results:

• Sub1 is upregulated in aged hearts and HFpEF models.
• Cardiac Sub1 overexpression accelerates aging and exacerbates diastolic dysfunction, while Sub1 knockdown delays aging and ameliorates HFpEF.
• Sub1 stabilizes p53 through interaction with TAF9b and AROS, promoting cardiomyocyte senescence.
• Disruption of the Sub1-p53 interaction reduces cardiomyocyte senescence.

Conclusions:

• Sub1 is a key contributor to aging-associated HFpEF.
• Sub1-mediated stabilization of p53 is a critical mechanism linking cardiac aging to HFpEF.
• Targeting the Sub1-p53 interaction may offer a therapeutic strategy for HFpEF.