ORCID Profile
0000-0003-3724-4132
Current Organisation
Rutgers New Jersey Medical School
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Publisher: Springer Science and Business Media LLC
Date: 09-12-2014
DOI: 10.1038/NCOMMS6705
Abstract: Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue s les from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70 signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.BBALIP.2017.12.003
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 16weeks. 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.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-12-2021
Abstract: Exercise-induced ROS mediates antioxidant defense to attenuate oxidative damage and insulin resistance in aging and obesity.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.YJMCC.2009.08.020
Abstract: Atrial fibrillation (AF) is commonly associated with chronic dilatation of the left atrium, both in human disease and animal models. The immediate signaling enzyme phospholipase C (PLC) is activated by mechanical stretch to generate the Ca2+-releasing messenger inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) and sn-1,2-diacylglycerol (DAG), an activator of protein kinase C subtypes. There is also evidence that heightened activity of PLC, caused by the receptor coupling protein Gq, can contribute to atrial remodelling. We examined PLC activation in right and left atrial appendage from patients with mitral valve disease (VHD) and in a mouse model of dilated cardiomyopathy caused by transgenic overexpression of the stress-activated protein kinase, mammalian sterile 20 like kinase 1 (Mst1) (Mst1-TG). PLC activation was heightened 6- to 10-fold in atria from VHD patients compared with right atrial tissue from patients undergoing coronary artery bypass surgery (CABG) and was also heightened in the dilated atria from Mst1-TG. PLC activation in human left atrial appendage and in mouse left atria correlated with left atrial size, implying a relationship between PLC activation and chronic dilatation. Dilated atria from human and mouse showed heightened expression of PLCbeta1b, but not of other PLC subtypes. PLCbeta1b, but not PLCbeta1a, caused apoptosis when overexpressed in neonatal rat cardiomyocytes, suggesting that PLCbeta1b may contribute to chamber dilatation. The activation of PLCbeta1b is a possible therapeutic target to limit atrial remodelling in VHD patients.
Publisher: Informa UK Limited
Date: 02-01-2016
Publisher: Wiley
Date: 20-07-2016
DOI: 10.1113/JP272512
Publisher: American Association for the Advancement of Science (AAAS)
Date: 27-08-2010
Publisher: Wiley
Date: 30-05-2019
DOI: 10.1111/BPH.14674
Publisher: Elsevier BV
Date: 09-2009
Publisher: Elsevier BV
Date: 04-2010
No related grants have been discovered for Junichi Sadoshima.