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Myocardial infarction elevates endoplasmic reticulum stress and protein aggregation in heart as well as brain

Nirjal Mainali1,2, Xiao Li3, Xianwei Wang3

  • 1Bioinformatics Program, University of Arkansas at Little Rock and University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

Molecular and Cellular Biochemistry
|November 3, 2023
PubMed

Insights

Myocardial infarction (MI) increases protein aggregation in the heart and brain, potentially causing Alzheimer's disease-like cognitive impairment. Mesenchymal stem cell exosomes can reduce this aggregation and endoplasmic reticulum stress.

Area of Science:

  • Cardiovascular Biology
  • Neuroscience
  • Protein Biochemistry

Background:

  • Cardiovascular diseases, like myocardial infarction (MI), are leading causes of death globally.
  • Protein aggregation is linked to aging and neurodegenerative diseases such as Alzheimer's disease (AD).
  • Previous research indicated elevated protein aggregation in aging and hypertensive mouse hearts, but MI's impact on heart and brain aggregation was unknown.

Purpose of the Study:

  • To investigate the effects of experimental myocardial infarction (MI) on protein aggregation in mouse hearts and brains.
  • To identify protein constituents within these aggregates.
  • To evaluate the potential of mesenchymal stem cell (MSC) exosomes in mitigating MI-induced aggregation and associated stress.

Main Methods:

  • Induction of MI in mice via left coronary artery (LCA) ligation, with sham-MI as controls.
  • Isolation and purification of detergent-insoluble aggregates from infarcted heart tissue and whole cerebra 7 days post-MI.
  • Quantification of protein constituents using high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • Assessment of endoplasmic reticulum (ER) stress markers (GRP78, ATF6, P-PERK).

Main Results:

  • Infarct heart tissue exhibited significantly higher levels of protein aggregates (2.5- to 10-fold increase) compared to non-infarct or sham-MI tissues.
  • Protein components of MI-induced cerebral aggregates showed considerable overlap with those found in human AD brains.
  • MSC exosome treatment reduced cardiac aggregation by approximately 60% and attenuated ER stress markers in heart and brain by 50-75%.
  • MI elevated aggregate constituents common in AD, including proteasomal subunits, heat-shock proteins, and apolipoproteins.

Conclusions:

  • Experimental MI significantly increases protein aggregation in both the heart and brain of mice.
  • MI-induced brain aggregation shares constituents with human Alzheimer's disease, suggesting a link to cognitive impairment.
  • MSC exosome therapy effectively reduces cardiac aggregation and alleviates ER stress in both cardiac and brain tissues post-MI.

Keywords:
AgingAlzheimer’s diseaseEndoplasmic reticulum stress (ER stress)ExosomesHypoxiaMyocardial infarction (MI)Protein aggregation

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