Cardiac-Specific Inactivation of LPP3 in Mice Leads to Myocardial Dysfunction and Heart Failure
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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This work was supported by American Heart Association Scientist Development Grant 10SDG4190036 to Dr. Panchatcharam; Louisiana State University Health Sciences – Shreveport Intramural Grant 110101074A to Dr. Miriyala; National Institutes of Health Grants HL098435 and HL133497 to Dr. Orr and R00 HL122354 to Dr. Bhuiyan. Funding to pay the publication charges for this article was provided by Dr. Panchatcharam.
Supplementary material related to this article can be found online at https://doi.org/10.1016/j.redox.2017.09.015.
Chandra, Mini; Escalante-Alcalde, Diana; Bhuiyan, Shenuarin; Orr, Anthony Wayne; Kevil, Christopher; Morris, Andrew J.; Nam, Hyung; Dominic, Paari; McCarthy, Kevin J.; Miriyala, Sumitra; and Panchatcharam, Manikandan, "Cardiac-Specific Inactivation of LPP3 in Mice Leads to Myocardial Dysfunction and Heart Failure" (2017). Internal Medicine Faculty Publications. 116.
1-s2.0-S2213231717306572-mmc1.mp4 (2915 kB)
Video 1. Video shows the beating neonatal cardiomyocyte derived from Plpp3fl mice.
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Published in Redox Biology, v. 14, p. 261-271.
© 2017 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/)