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Age-related proteostatic imbalance exacerbates heart failure with preserved ejection fraction pathogenesis in old mice

ABSTRACT: Abstract: Heart failure with preserved ejection fraction (HFpEF) is a leading cause of hospitalization and death in the elderly. While aging strongly increases the incidence of HFpEF, the specific influences of aging on HFpEF at molecular and pathophysiological levels remain unclear. Here, we show that aged mice, when subjected to chronic metabolic and hypertensive stress (2-hit stress), develop an aggravated cardiometabolic HFpEF phenotype compared to younger counterparts. Aged HFpEF mice also display unique pathological characteristics reminiscent of those found in HFpEF patients. We demonstrate that age-related dysfunction in protein quality control (PQC) exacerbates proteostatic stress in HFpEF. Specifically, we demonstrate that increased protein synthesis induced by 2-hit stress combines with age-related impairment in protein degradation in aged HFpEF hearts, culminating in the accumulation of protein aggregates. These findings underscore the importance of incorporating aging into preclinical HFpEF models and support the therapeutic potential of targeting PQC mechanisms to ameliorate disease outcomes.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Ricard Rodriguez-Mias

LAB HEAD: Judit Villen

PROVIDER: PXD051715 | Pride | 2025-01-10

REPOSITORIES: pride

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			Action	DRS
	39860_e06597_A_5_4_proteome_2h_reinj.fasta	Fasta
	39860_e06597_A_5_4_proteome_2h_reinj.mzML	Mzml
	39860_e06597_A_5_4_proteome_2h_reinj.mzid.gz	Mzid
	39860_e06597_A_5_4_proteome_2h_reinj.pepXML	Pepxml
	39860_e06597_A_5_4_proteome_2h_reinj.raw	Raw

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Project description:Aims: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. Methods&Results: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF.

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Age-related proteostatic imbalance exacerbates heart failure with preserved ejection fraction pathogenesis in old mice

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