Autotaxin‐LPA‐LPP3 axis regulates mitochondrial respiration prompting myocardial dysfunction

Abstract

Background and ObjectiveAcute myocardial infarction (AMI) and ischemic heart disease are the two most prevalent causes of morbidity and mortality in the western world. Lysophosphatidic acid (LPA) a pro‐inflammatory, pro‐thrombotic bioactive glycerophospholipid plays a well‐known role in atherosclerotic disease; its role in myocardial dysfunction remains virtually unexplored. Following AMI, serum LPA concentration increases six‐fold over control subjects. Since LPA has a rapid turnover in the circulation, LPA production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin.In contrast, LPP3 catalyzes LPA dephosphorylation to generate lipid products that are not receptor active. The steady state of local and circulating LPA is balanced between these opposing pathways of LPA synthesis and degradation. The goal of this study was to determine the role of the autotaxin‐LPA‐LPP3 axis in myocardial dysfunction along with cardiomyocyte responses.MethodsTo study the role of the autotaxin‐LPA‐LPP3 axis in the myocardium, we used human induced pluripotent stem cell (IPS) cardiomyocytes and generated a cardiac‐specific Plpp3 deficient mouse strain. Mitochondrial bioenergetics was measured using the Seahorse XF24 analyzer.ResultsOur results show that exposure to LPA significantly decreased oxygen consumption rate (OCR; P<0.001) and increased extracellular acidification rate (ECAR; P<0.001) in IPS cardiomyocytes. Similar results were seen after subjecting the IPS cardiomyocytes to hypoxia where in the addition of autotaxin inhibitors had the reverse effect on OCR (P<0.001) and ECAR (P<0.001). LPA receptors blockade with pan‐Brp‐LPA restored the mitochondrial OCR (P<0.001) and decreased the ECAR (P<0.001). Generation of Plpp3 knockout mice (Plpp3Δ) showed increased mortality ~8 months. Plpp3Δ myocardium showed a distorted intercalated disc with damaged mitochondria with disorganized cristae and amorphous matrix densities as compared to lpp3fl in transmission electron microscopy. Lack of LPP3 resulted in deteriorating cardiac function. Plpp3Δ cardiomyocyte exposure to LPA significantly decreased oxygen consumption rate (OCR; P<0.001) and increased extracellular acidification rate (ECAR; P<0.001). Together these findings show that the absence of LPP3 increases LPA signaling and results in impaired mitochondrial function.Discussion and ConclusionsThe results presented in this study indicate that the autotaxin‐LPA‐LPP3 axis plays a critical role in the mitochondrial respiration and loss of LPP3 in cardiomyocytes from Plpp3Δ mice further confirms the impairment of myocardial function. Importantly, we demonstrate that autotaxin‐LPA‐LPP3 axis regulates mitochondrial respiration to limit myocardial function.Support or Funding InformationNational Institutes of Health Grants 1P20GM121307‐01A1 (Dr. Kevil) Sub‐Project ID: 8571 to Dr. Panchatcharam.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.