PMID- 30702345
OWN - NLM
STAT- MEDLINE
DCOM- 20200218
LR  - 20200930
IS  - 1522-1504 (Electronic)
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 316
IP  - 4
DP  - 2019 Apr 1
TI  - Small-hairpin RNA and pharmacological targeting of neutral sphingomyelinase 
      prevent diaphragm weakness in rats with heart failure and reduced ejection 
      fraction.
PG  - L679-L690
LID - 10.1152/ajplung.00516.2018 [doi]
AB  - Heart failure with reduced ejection fraction (HFREF) increases neutral 
      sphingomyelinase (NSMase) activity and mitochondrial reactive oxygen species 
      (ROS) emission and causes diaphragm weakness. We tested whether a systemic 
      pharmacological NSMase inhibitor or short-hairpin RNA (shRNA) targeting NSMase 
      isoform 3 (NSMase3) would prevent diaphragm abnormalities induced by HFREF caused 
      by myocardial infarction. In the pharmacological intervention, we used 
      intraperitoneal injection of GW4869 or vehicle. In the genetic intervention, we 
      injected adeno-associated virus serotype 9 (AAV9) containing shRNA targeting 
      NSMase3 or a scrambled sequence directly into the diaphragm. We also studied acid 
      sphingomyelinase-knockout mice. GW4869 prevented the increase in diaphragm 
      ceramide content, weakness, and tachypnea caused by HFREF. For example, maximal 
      specific forces (in N/cm(2)) were vehicle [sham 31 +/- 2 and HFREF 26 +/- 2 ( P < 
      0.05)] and GW4869 (sham 31 +/- 2 and HFREF 31 +/- 1). Respiratory rates were (in 
      breaths/min) vehicle [sham 61 +/- 3 and HFREF 84 +/- 11 ( P < 0.05)] and GW4869 (sham 
      66 +/- 2 and HFREF 72 +/- 2). AAV9-NSMase3 shRNA prevented heightening of diaphragm 
      mitochondrial ROS and weakness [in N/cm(2), AAV9-scrambled shRNA: sham 31 +/- 2 and 
      HFREF 27 +/- 2 ( P < 0.05); AAV9-NSMase3 shRNA: sham 30 +/- 1 and HFREF 30 +/- 1] but 
      displayed tachypnea. Both wild-type and ASMase-knockout mice with HFREF displayed 
      diaphragm weakness. Our study suggests that activation of NSMase3 causes 
      diaphragm weakness in HFREF, presumably through accumulation of ceramide and 
      elevation in mitochondrial ROS. Our data also reveal a novel inhibitory effect of 
      GW4869 on tachypnea in HFREF likely mediated by changes in neural control of 
      breathing.
FAU - Coblentz, Philip D
AU  - Coblentz PD
AD  - Department of Applied Physiology and Kinesiology, College of Health and Human 
      Performance, University of Florida , Gainesville, Florida.
FAU - Ahn, Bumsoo
AU  - Ahn B
AD  - Department of Applied Physiology and Kinesiology, College of Health and Human 
      Performance, University of Florida , Gainesville, Florida.
FAU - Hayward, Linda F
AU  - Hayward LF
AD  - Department of Physiological Sciences, College of Veterinary Medicine, University 
      of Florida , Gainesville, Florida.
FAU - Yoo, Jeung-Ki
AU  - Yoo JK
AD  - Department of Applied Physiology and Kinesiology, College of Health and Human 
      Performance, University of Florida , Gainesville, Florida.
FAU - Christou, Demetra D
AU  - Christou DD
AUID- ORCID: 0000-0002-9710-6666
AD  - Department of Applied Physiology and Kinesiology, College of Health and Human 
      Performance, University of Florida , Gainesville, Florida.
FAU - Ferreira, Leonardo F
AU  - Ferreira LF
AUID- ORCID: 0000-0001-6581-5882
AD  - Department of Applied Physiology and Kinesiology, College of Health and Human 
      Performance, University of Florida , Gainesville, Florida.
LA  - eng
GR  - R00 HL098453/HL/NHLBI NIH HHS/United States
GR  - R01 HL130318/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190131
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 0 (Aniline Compounds)
RN  - 0 (Benzylidene Compounds)
RN  - 0 (GW 4869)
RN  - 0 (RNA, Small Interfering)
RN  - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
SB  - IM
MH  - Aniline Compounds/pharmacology
MH  - Animals
MH  - Benzylidene Compounds/pharmacology
MH  - Diaphragm/enzymology/*physiopathology
MH  - Disease Models, Animal
MH  - Heart Failure/genetics/*physiopathology/therapy
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Muscle Weakness/genetics/physiopathology/*prevention & control
MH  - RNA, Small Interfering/*genetics
MH  - Rats
MH  - Rats, Wistar
MH  - Sphingomyelin Phosphodiesterase/*antagonists & inhibitors/deficiency/*genetics
MH  - Stroke Volume/genetics/physiology
PMC - PMC6483012
OTO - NOTNLM
OT  - ceramide
OT  - mitochondria
OT  - myocardial infarction
OT  - oxidants
OT  - skeletal muscle
OT  - tachypnea
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2019/02/01 06:00
MHDA- 2020/02/19 06:00
PMCR- 2020/04/01
CRDT- 2019/02/01 06:00
PHST- 2019/02/01 06:00 [pubmed]
PHST- 2020/02/19 06:00 [medline]
PHST- 2019/02/01 06:00 [entrez]
PHST- 2020/04/01 00:00 [pmc-release]
AID - L-00516-2018 [pii]
AID - 10.1152/ajplung.00516.2018 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2019 Apr 1;316(4):L679-L690. doi: 
      10.1152/ajplung.00516.2018. Epub 2019 Jan 31.