Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure

Jason L. Guichard, Michael Rogowski, Giulio Agnetti, Lianwu Fu, Pamela Powell, Chih Chang Wei, James Collawn, Louis J. Dell’Italia

Research output: Research - peer-reviewArticle

Abstract

Heart failure due to chronic volume overload (VO) in rats and humans is characterized by disorganization of the cardiomyocyte desmin/mitochondrial network. Here, we tested the hypothesis that desmin breakdown is an early and continuous process throughout VO. Male Sprague-Dawley rats had aortocaval fistula (ACF) or sham surgery and were examined 24 h and 4 and 12 wk later. Desmin/mitochondrial ultrastructure was examined by transmission electron microscopy (TEM) and immunohistochemistry (IHC). Protein and kinome analysis were performed in isolated cardiomyocytes, and desmin cleavage was assessed by mass spectrometry in left ventricular (LV) tissue. Echocardiography demonstrated a 40% decrease in the LV mass-tovolume ratio with spherical remodeling at 4 wk with ACF and LV systolic dysfunction at 12 wk. Starting at 24 h and continuing to 4 and 12 wk, with ACF there is TEM evidence of extensive mitochondrial clustering, IHC evidence of disorganization associated with desmin breakdown, and desmin protein cleavage verified by Western blot analysis and mass spectrometry. IHC results revealed that ACF cardiomyocytes at 4 and 12 wk had perinuclear translocation of αB-crystallin from the Z disk with increased α, β-unsaturated aldehyde 4-hydroxynonelal. Use of protein markers with verification by TUNEL staining and kinome analysis revealed an absence of cardiomyocyte apoptosis at 4 and 12 wk of ACF. Significant increases in protein indicators of mitophagy were countered by a sixfold increase in p62/sequestosome-1, which is indicative of an inability to complete autophagy. An early and continuous disruption of the desmin/mitochondrial architecture, accompanied by oxidative stress and inhibition of apoptosis and mitophagy, suggests its causal role in LV dilatation and systolic dysfunction in VO. NEW & NOTEWORTHY This study provides new evidence of early onset (24 h) and continuous (4-12 wk) desmin misarrangement and disruption of the normal sarcomeric and mitochondrial architecture throughout the progression of volume overload heart failure, suggesting a causal link between desmin cleavage and mitochondrial disorganization and damage.

LanguageEnglish (US)
PagesH32-H45
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume313
Issue number1
DOIs
StatePublished - 2017

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Desmin
Heart Failure
Fistula
Cardiac Myocytes
Proteins
Immunohistochemistry
Mitochondrial Degradation
Transmission Electron Microscopy
Mass Spectrometry
Apoptosis
Crystallins
Autophagy
In Situ Nick-End Labeling
Left Ventricular Dysfunction
Aldehydes
Sprague Dawley Rats
Cluster Analysis
Echocardiography
Dilatation
Oxidative Stress

Keywords

  • Apoptosis
  • Cardiomyocyte
  • Desmin
  • Heart failure
  • Mitochondria

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure. / Guichard, Jason L.; Rogowski, Michael; Agnetti, Giulio; Fu, Lianwu; Powell, Pamela; Wei, Chih Chang; Collawn, James; Dell’Italia, Louis J.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 313, No. 1, 2017, p. H32-H45.

Research output: Research - peer-reviewArticle

Guichard, Jason L. ; Rogowski, Michael ; Agnetti, Giulio ; Fu, Lianwu ; Powell, Pamela ; Wei, Chih Chang ; Collawn, James ; Dell’Italia, Louis J./ Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure. In: American Journal of Physiology - Heart and Circulatory Physiology. 2017 ; Vol. 313, No. 1. pp. H32-H45
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