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

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.

Lysophosphatidic Acid Is Associated With Cardiac Dysfunction and Hypertrophy by Suppressing Autophagy via the LPA3/AKT/mTOR Pathway

“…Lipid phosphate phosphatase 3 (LPP3), is a major enzyme that dephosphorylates LPA. Cardiac-specific inactivation of LPP3 displays cardiac hypertrophy and myocardial dysfunction in mice, indicating that the LPA/LPP3-signaling play an important role in normal function of cardiomyocytes ( Chandra et al, 2018 ). These data indirectly support the findings in the current study.…”

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

“…Mitochondrial oxygen consumption rate was measured with an XF24 Extracellular Flux Analyzer (Seahorse Biosciences, North Billerica, MA) by methods as described previously 22, 23, 24. Heart mitochondria were isolated using MS‐EGTA buffer (225 mmol/L mannitol, 75 mmol/L sucrose, 5 mmol/L HEPES, and 1 mmol/L EGTA, pH 7.4) by differential centrifugation as described above.…”

Dynamics of cardiomyocyte transcriptome and chromatin landscape demarcates key events of heart development

“…Among the 14 genes that were commonly down-regulated in all three mutants, four belonged to green (nid1b, papss2b, vcanb, bmp3) and two to salmon (plppr3a, spon1b) modules. Genes including vcan, plppr3a, and Bmp family were previously found to play a crucial role in heart morphogenesis and function (Marques and Yelon 2009;Kern et al 2010;Chandra et al 2018). Similarly, comparing chromatin accessibility data revealed that 21% (73 regions), 24% (13 regions), and 29% (five regions) of proximal NFRs that showed decreased acces-sibility in gata5 tm236a/tm236a , hand2 s6/s6 , and tbx5a m21/ m21 mutants were located within the proximal promoters of genes belonging to cardiac modules (Fig.…”