Impaired Extracellular Proteostasis in Patients with Heart Failure

Marisol Gouveia; Manuel Teixeira; Cristine Schmidt; Mário Lopes; Dário Trindade; Sandra Magalhães; Ana Gabriela Henriques; Alexandra Nunes; Mário Santos; Sandra Vieira; Fernando Ribeiro

doi:10.1016/j.arcmed.2023.02.001

Impaired Extracellular Proteostasis in Patients with Heart Failure

Arch Med Res. 2023 Apr;54(3):211-222. doi: 10.1016/j.arcmed.2023.02.001. Epub 2023 Feb 14.

Affiliations

¹ Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal. Electronic address: marisolgouveia@ua.pt.
² Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal.
³ Surgery and Physiology Department, Faculty of Medicine, University of Porto, Porto, Portugal; Research Center in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal.
⁴ School of Health Sciences, University of Aveiro, Aveiro, Portugal.
⁵ Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal; Centre for Research in Ceramics and Composite Materials, Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Portugal.
⁶ Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal; Serviço de Cardiologia, Hospital Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal; Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.
⁷ Institute of Biomedicine, School of Health Sciences, University of Aveiro, Aveiro, Portugal.

PMID: 36797157
DOI: 10.1016/j.arcmed.2023.02.001

Abstract

Background: Proteostasis impairment and the consequent increase of amyloid burden in the myocardium have been associated with heart failure (HF) development and poor prognosis. A better knowledge of the protein aggregation process in biofluids could assist the development and monitoring of tailored interventions.

Aim: To compare the proteostasis status and protein's secondary structures in plasma samples of patients with HF with preserved ejection fraction (HFpEF), patients with HF with reduced ejection fraction (HFrEF), and age-matched individuals.

Methods: A total of 42 participants were enrolled in 3 groups: 14 patients with HFpEF, 14 patients with HFrEF, and 14 age-matched individuals. Proteostasis-related markers were analyzed by immunoblotting techniques. Fourier Transform Infrared (FTIR) Spectroscopy in Attenuated Total Reflectance (ATR) was applied to assess changes in the protein's conformational profile.

Results: Patients with HFrEF showed an elevated concentration of oligomeric proteic species and reduced clusterin levels. ATR-FTIR spectroscopy coupled with multivariate analysis allowed the discrimination of HF patients from age-matched individuals in the protein amide I absorption region (1700-1600 cm^-1), reflecting changes in protein conformation, with a sensitivity of 73 and a specificity of 81%. Further analysis of FTIR spectra showed significantly reduced random coils levels in both HF phenotypes. Also, compared to the age-matched group, the levels of structures related to fibril formation were significantly increased in patients with HFrEF, whereas the β-turns were significantly increased in patients with HFpEF.

Conclusion: Both HF phenotypes showed a compromised extracellular proteostasis and different protein conformational changes, suggesting a less efficient protein quality control system.

Keywords: ATR-FTIR spectroscopy; Clusterin; HFpEF; HFrEF; Protein aggregation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Heart Failure*
Humans
Phenotype
Prognosis
Proteostasis
Stroke Volume