p53-Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction

Area of Science:

• Cardiology
• Aging Research
• Molecular Biology

Background:

• Heart failure with preserved ejection fraction (HFpEF) affects 50% of heart failure patients, with age and gender biases.
• While HFpEF is common in the elderly, young patients are increasingly observed, necessitating research into underlying mechanisms.
• The role of aging in HFpEF pathogenesis requires further elucidation.

Purpose of the Study:

• To investigate the role of aging and p53 activation in the development of HFpEF.
• To determine how telomere shortening and mitochondrial function are affected in an aging HFpEF model.

Main Methods:

• Induction of HFpEF in wild-type and telomerase RNA component knockout mice using a high-fat diet and Nω-Nitro-L-arginine methyl ester hydrochloride.
• Assessment of cardiac function, histological changes, and mitochondrial respiration.
• Utilized myocardial-specific p53 knockout mice to evaluate p53's role.

Main Results:

• HFpEF developed equally in male and female mice, with cardiac wall thickening preceding diastolic dysfunction.
• Accelerated HFpEF onset occurred in telomerase RNA component knockout mice compared to wild-type.
• Mitochondrial respiration shifted from compensatory to dysfunctional states in a p53-dependent manner; loss of p53 delayed HFpEF onset.

Conclusions:

• p53 activation is a key factor in HFpEF pathogenesis.
• Short telomere mice exhibit basal p53 activation and mitochondrial upregulation of mtDNA-encoded genes.
• Inhibition of myocardial p53 activation delays HFpEF development in a murine model.