期刊
JOURNAL OF NEUROTRAUMA
卷 36, 期 6, 页码 950-961出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/neu.2017.5624
关键词
autophagy-lysosomal machinery; cardiac atrophy; magnetic resonance imaging; spinal cord injury; ubiquitin-proteasome system
资金
- Heart and Stroke Foundation of Canada
- Blusson Integrative Cures Partnership [17R23888]
- Michael Smith Foundation for Health Research [16113, 17R22611]
- Craig H. Neilsen Foundation [384825]
- Frederick Banting and Charles Best Canada Graduate Scholarship
- Vancouver Coastal Health-University of British Columbia MD/PhD Studentship from the Canadian Institutes of Health Research
- Four Year Fellowship from the University of British Columbia
- Rick Hansen Institute [17R22611]
Spinal cord injury (SCI) causes autonomic dysfunction, altered neurohumoral control, profound hemodynamic changes, and an increased risk of heart disease. In this prospective study, we investigated the cardiac consequences of chronic experimental SCI in rats by combining cutting edge in vivo techniques (magnetic resonance imaging [MRI] and left-ventricular [LV] pressure-volume catheterization) with histological and molecular assessments. Twelve weeks post-SCI, MRI-derived structural indices and in vivo LV catheterization-derived functional indices indicated the presence of LV atrophy (LV mass in Control vs. SCI=525 +/- 38.8 vs. 413 +/- 28.6mg, respectively; p=0.0009), reduced ventricular volumes (left-ventricular end-diastolic volume in Control vs. SCI=364 +/- 44 vs. 221 +/- 35L, respectively; p=0.0004), and contractile dysfunction (end-systolic pressure-volume relationship in Control vs. SCI=1.31 +/- 0.31 vs. 0.76 +/- 0.11mm Hg/L, respectively; p=0.0045). Cardiac atrophy and contractile dysfunction in SCI were accompanied by significantly lower blood pressure, reduced circulatory norepinephrine, and increased angiotensin II. At the cellular level, we found the presence of reduced cardiomyocyte size and increased expression of angiotensin II type 1 receptors and transforming growth factor-beta receptors (TGF- receptor 1 and 2) post-SCI. Importantly, we found more than a two-fold increase in muscle ring finger-1 and Beclin-1 protein level following SCI, indicating the upregulation of the ubiquitin-proteasome system and autophagy-lysosomal machinery. Our data provide novel evidence that SCI-induced cardiomyocyte atrophy and systolic cardiac dysfunction are accompanied by an upregulation of proteolytic pathways, the activation of which is likely due to loss of trophic support from the sympathetic nervous system, neuromechanical unloading, and altered neurohumoral pathways.
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