Diaphragm dysfunction in heart failure is accompanied by increases in neutral sphingomyelinase activity and ceramide content. (4th March 2014)

• Record Type: Journal Article
• Authors: Empinado, Hyacinth M.; Deevska, Gergana M.; Nikolova‐Karakashian, Mariana; Yoo, Jeung‐Ki; Christou, Demetra D.; Ferreira, Leonardo F.
• Is Part Of: European journal of heart failure. Volume 16:Number 5(2014)
• Page Start: 519
• Page End: 525
• Publication Date: 2014-03-04
• Subjects: Heart failure -- Periodicals; Heart Failure -- Periodicals; Insuffisance cardiaque -- Périodiques; Heart failure; Periodicals; 616.129005
• DOI: 10.1002/ejhf.73
• Languages: English
• ISSNs: 1388-9842

Abstract

<abstract abstract-type="main" id="ejhf73-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ejhf73-sec-0001" sec-type="section"> <title>Aims</title> <p id="ejhf73-para-0001">Chronic heart failure (CHF) causes inspiratory (diaphragm) muscle weakness and fatigue that contributes to dyspnoea and limited physical capacity in patients. However, the mechanisms that lead to diaphragm dysfunction in CHF remain poorly understood. Cytokines and angiotensin II are elevated in CHF and stimulate the activity of the enzyme sphingomyelinase (SMase) and accumulation of its reaction product ceramide. In the diaphragm, SMase or ceramide exposure <italic>in vitro</italic> causes weakness and fatigue. Thus, elevated SMase activity and ceramide content have been proposed as mediators of diaphragm dysfunction in CHF. In the present study, we tested the hypotheses that diaphragm dysfunction was accompanied by increases in diaphragm SMase activity and ceramide content.</p> </sec> <sec id="ejhf73-sec-0002" sec-type="section"> <title>Methods and results</title> <p id="ejhf73-para-0002">Myocardial infarction was used to induce CHF in rats. We measured diaphragm isometric force, SMase activity by high‐performance liquid chromatography, and ceramide subspecies and total ceramide using mass spectrometry. Diaphragm force was depressed and fatigue accelerated by CHF. Diaphragm neutral SMase activity was increased by 20% in CHF, while acid SMase activity was unchanged. We also found that CHF increased the content of C<sub>18</sub>–, C<sub>20</sub>–, and C<sub>24</sub>‐ceramide subspecies and total ceramide. Downstream of ceramide degradation, diaphragm sphingosine was unchanged, and sphingosine‐1‐phosphate level was increased in CHF.</p> </sec> <sec id="ejhf73-sec-0003" sec-type="section"> <title>Conclusion</title> <p id="ejhf73-para-0003">Our major novel finding was that diaphragm dysfunction in CHF rats was accompanied by higher diaphragm neutral SMase activity, which is expected to cause the observed increase in diaphragm ceramide content.</p> </sec> </abstract>