Part 2 of Age-related proteostatic imbalance exacerbates heart failure with preserved ejection fraction pathogenesis in old mice

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 potentials of targeting PQC mechanisms to ameliorate disease outcomes. The deposited data are lc-ms data acquired on the Thermo QEx-Plus system. For any questions, please contact mike kinter mike-kinter at omrf.org This upload contains the second part of the data. The majority of the data and a complete list of authors can be found in 10.5281/zenodo.10993216