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Redox Biol. 2018 Apr;14:261-271. doi: 10.1016/j.redox.2017.09.015. Epub 2017 Sep 28.

Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure.

Author information

1
Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, USA.
2
División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, Mexico.
3
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, USA.
4
Division of Cardiovascular Medicine, University of Kentucky, Lexington, USA.
5
Department of Pharmacology and Toxicology, Louisiana State University Health Sciences Center, Shreveport, USA.
6
Division of Cardiology, Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA.
7
Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, USA; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, USA.
8
Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, USA. Electronic address: smiriy@lsuhsc.edu.
9
Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, USA. Electronic address: mpanch@lsuhsc.edu.

Abstract

Lipid Phosphate phosphatase 3 (LPP3), encoded by the Plpp3 gene, is an enzyme that dephosphorylates the bioactive lipid mediator lysophosphatidic acid (LPA). To study the role of LPP3 in the myocardium, we generated a cardiac specific Plpp3 deficient mouse strain. Although these mice were viable at birth in contrast to global Plpp3 knockout mice, they showed increased mortality ~ 8 months. LPP3 deficient mice had enlarged hearts with reduced left ventricular performance as seen by echocardiography. Cardiac specific Plpp3 deficient mice had longer ventricular effective refractory periods compared to their Plpp3 littermates. We observed that lack of Lpp3 enhanced cardiomyocyte hypertrophy based on analysis of cell surface area. We found that lack of Lpp3 signaling was mediated through the activation of Rho and phospho-ERK pathways. There are increased levels of fetal genes Natriuretic Peptide A and B (Nppa and Nppb) expression indicating myocardial dysfunction. These mice also demonstrate mitochondrial dysfunction as evidenced by a significant decrease (P < 0.001) in the basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity as measured through mitochondrial bioenergetics. Histology and transmission electron microscopy of these hearts showed disrupted sarcomere organization and intercalated disc, with a prominent disruption of the cristae and vacuole formation in the mitochondria. Our findings suggest that LPA/LPP3-signaling nexus plays an important role in normal function of cardiomyocytes.

KEYWORDS:

Heart failure; Lipid phosphate phosphatase; Lysophosphatidic acid

PMID:
28982073
PMCID:
PMC5635346
DOI:
10.1016/j.redox.2017.09.015
[Indexed for MEDLINE]
Free PMC Article

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