Distinct lipidomic profiles in models of physiological and pathological cardiac remodeling,and potential therapeutic strategies |
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Authors: | Yow Keat Tham Kevin Huynh Natalie A. Mellett Darren C. Henstridge Helen Kiriazis Jenny Y.Y. Ooi Aya Matsumoto Natalie L. Patterson Junichi Sadoshima Peter J. Meikle Julie R. McMullen |
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Affiliation: | 1. Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia;2. Department of Medicine, Monash University, Clayton, VIC 3800, Australia;3. Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA;4. Department of Physiology, Monash University, Clayton, VIC 3800, Australia |
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Abstract: | Cardiac myocyte membranes contain lipids which remodel dramatically in response to heart growth and remodeling. Lipid species have both structural and functional roles. Physiological and pathological cardiac remodeling have very distinct phenotypes, and the identification of molecular differences represent avenues for therapeutic interventions. Whether the abundance of specific lipid classes is different in physiological and pathological models was largely unknown. The aim of this study was to determine whether distinct lipids are regulated in settings of physiological and pathological remodeling, and if so, whether modulation of differentially regulated lipids could modulate heart size and function. Lipidomic profiling was performed on cardiac-specific transgenic mice with 1) physiological cardiac hypertrophy due to increased Insulin-like Growth Factor 1 (IGF1) receptor or Phosphoinositide 3-Kinase (PI3K) signaling, 2) small hearts due to depressed PI3K signaling (dnPI3K), and 3) failing hearts due to dilated cardiomyopathy (DCM). In hearts of dnPI3K and DCM mice, several phospholipids (plasmalogens) were decreased and sphingolipids increased compared to mice with physiological hypertrophy. To assess whether restoration of plasmalogens could restore heart size or cardiac function, dnPI3K and DCM mice were administered batyl alcohol (BA; precursor to plasmalogen biosynthesis) in the diet for 16 weeks. BA supplementation increased a major plasmalogen species (p18:0) in the heart but had no effect on heart size or function. This may be due to the concurrent reduction in other plasmalogen species (p16:0 and p18:1) with BA. Here we show that lipid species are differentially regulated in settings of physiological and pathological remodeling. Restoration of lipid species in the failing heart warrants further examination. |
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Keywords: | BA batyl alcohol CA chimyl alcohol DCM dilated cardiomyopathy IGF1 Insulin-like Growth Factor 1 Mst1 Mammalian Sterile 20-like Kinase 1 PI3K Phosphoinositide 3-Kinase SA selachyl alcohol Lipids Physiological cardiac hypertrophy Plasmalogens Heart failure Dietary supplement |
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