Journal article
Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure
Redox biology, Vol.14, pp.261-271
04/2018
DOI: 10.1016/j.redox.2017.09.015
PMCID: PMC5635346
PMID: 28982073
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.
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•PLPP3 plays a prominent role in the heart compared to other isoforms of PLPP.•Lack of PLPP3 results in deteriorating cardiac function.•PLPP3 regulates LPA signaling in cardiomyocytes.•Presence of PLPP3 is required for optimal mitochondrial function.•Increased free radical production is mitigated with activated PLPP3.
Details
- Title: Subtitle
- Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure
- Creators
- Mini Chandra - Louisiana State University Health Sciences Center ShreveportDiana Escalante-Alcalde - Universidad Nacional Autónoma de MéxicoMd. Shenuarin Bhuiyan - Louisiana State University Health Sciences Center ShreveportAnthony Wayne Orr - Louisiana State University Health Sciences Center ShreveportChristopher Kevil - Louisiana State University Health Sciences Center ShreveportAndrew J. Morris - University of KentuckyHyung Nam - Louisiana State University Health Sciences Center ShreveportPaari Dominic - Louisiana State University Health Sciences Center ShreveportKevin J. McCarthy - Louisiana State University Health Sciences Center ShreveportSumitra Miriyala - Louisiana State University Health Sciences Center ShreveportManikandan Panchatcharam - Louisiana State University Health Sciences Center Shreveport
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.14, pp.261-271
- DOI
- 10.1016/j.redox.2017.09.015
- PMID
- 28982073
- PMCID
- PMC5635346
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- Elsevier B.V
- Grant note
- name: American Heart Association Scientist Development, award: 10SDG4190036; name: Louisiana State University Health Sciences – Shreveport Intramural, award: 110101074A; DOI: 10.13039/100000002, name: National Institutes of Health, award: HL098435, HL133497, R00 HL122354
- Language
- English
- Date published
- 04/2018
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984367119402771
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