Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction

Himi Tripathi, Ahmed Al-Darraji, Mohamed Abo-Aly, Hsuan Peng, Elica Shokri, Lakshman Chelvarajan, Renee R. Donahue, Bryana M. Levitan, Erhe Gao, Gabriela Hernandez, Andrew J. Morris, Susan S. Smyth, Ahmed Abdel-Latif

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Objective: Acute myocardial infarction (AMI) initiates pathological inflammation which aggravates tissue damage and causes heart failure. Lysophosphatidic acid (LPA), produced by autotaxin (ATX), promotes inflammation and the development of atherosclerosis. The role of ATX/LPA signaling nexus in cardiac inflammation and resulting adverse cardiac remodeling is poorly understood. Approach and results: We assessed autotaxin activity and LPA levels in relation to cardiac and systemic inflammation in AMI patients and C57BL/6 (WT) mice. Human and murine peripheral blood and cardiac tissue samples showed elevated levels of ATX activity, LPA, and inflammatory cells following AMI and there was strong correlation between LPA levels and circulating inflammatory cells. In a gain of function model, lipid phosphate phosphatase-3 (LPP3) specific inducible knock out (Mx1-Plpp3Δ) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3fl/fl); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3Δ mice, cardiac functional recovery was reduced with corresponding increases in adverse cardiac remodeling and scar size (as assessed by echocardiography and Masson's Trichrome staining). To examine the effect of ATX/LPA nexus inhibition, we treated WT mice with the specific pharmacological inhibitor, PF8380, twice a day for 7 days post AMI. Inhibition of the ATX/LPA signaling nexus resulted in significant reduction in post-AMI inflammatory response, leading to favorable cardiac functional recovery, reduced scar size and enhanced angiogenesis. Conclusion: ATX/LPA signaling nexus plays an important role in modulating inflammation after AMI and targeting this mechanism represents a novel therapeutic target for patients presenting with acute myocardial injury.

Original languageEnglish
Pages (from-to)95-114
Number of pages20
JournalJournal of Molecular and Cellular Cardiology
Volume149
DOIs
StatePublished - Dec 2020

Bibliographical note

Publisher Copyright:
© 2020

Keywords

  • Autotaxin
  • Heart failure
  • Inflammation
  • Lysophosphatidic acid
  • Myocardial infarction

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction'. Together they form a unique fingerprint.

Cite this