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

doi:10.1016/j.yjmcc.2020.09.011

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 journal › Article › peer-review

9 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-Plpp3^Δ) showed higher systemic and cardiac inflammation after AMI compared to littermate controls (Mx1-Plpp3^fl/fl); and a corresponding increase in bone marrow progenitor cell count and proliferation. Moreover, in Mx1- Plpp3^Δ 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 language	English
Pages (from-to)	95-114
Number of pages	20
Journal	Journal of Molecular and Cellular Cardiology
Volume	149
DOIs	https://doi.org/10.1016/j.yjmcc.2020.09.011
State	Published - Dec 2020

Bibliographical note

Funding Information:
The UK Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant ( P30 CA177558 ) to the University of Kentucky Markey Cancer Center. This study used resources provided by the Lexington Veterans Affairs Medical Center.

Funding Information:
Dr. Abdel-Latif is supported by the University of Kentucky COBRE Early Career Program ( P20 GM103527 ) and the NIH Grant R01 HL124266 . This work was also supported by grants from the Department of Veterans Affairs : CX001550BX001984 and CX001550 and NIH/NHLBI : HL120507 and NIGMS GM103527 to AJM and SSS.

Funding Information:
Dr. Abdel-Latif is supported by the University of Kentucky COBRE Early Career Program (P20 GM103527) and the NIH Grant R01 HL124266. This work was also supported by grants from the Department of Veterans Affairs: CX001550BX001984 and CX001550 and NIH/NHLBI: HL120507 and NIGMS GM103527 to AJM and SSS.We are grateful for Jennifer Simkin for her assistance with the immunohistochemistry studies. We thank the University of Kentucky COBRE histology core for their assistance with the histological sections. The UK Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. This study used resources provided by the Lexington Veterans Affairs Medical Center.

Publisher Copyright:
© 2020

Keywords

Autotaxin
Heart failure
Inflammation
Lysophosphatidic acid
Myocardial infarction

ASJC Scopus subject areas

Molecular Biology
Cardiology and Cardiovascular Medicine

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10.1016/j.yjmcc.2020.09.011

Cite this

Tripathi, H., Al-Darraji, A., Abo-Aly, M., Peng, H., Shokri, E., Chelvarajan, L., R. Donahue, R., Levitan, B. M., Gao, E., Hernandez, G., Morris, A. J., Smyth, S. S., & Abdel-Latif, A. (2020). Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction. Journal of Molecular and Cellular Cardiology, 149, 95-114. https://doi.org/10.1016/j.yjmcc.2020.09.011

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title = "Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction",

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.",

keywords = "Autotaxin, Heart failure, Inflammation, Lysophosphatidic acid, Myocardial infarction",

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

note = "Funding Information: The UK Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant ( P30 CA177558 ) to the University of Kentucky Markey Cancer Center. This study used resources provided by the Lexington Veterans Affairs Medical Center. Funding Information: Dr. Abdel-Latif is supported by the University of Kentucky COBRE Early Career Program ( P20 GM103527 ) and the NIH Grant R01 HL124266 . This work was also supported by grants from the Department of Veterans Affairs : CX001550BX001984 and CX001550 and NIH/NHLBI : HL120507 and NIGMS GM103527 to AJM and SSS. Funding Information: Dr. Abdel-Latif is supported by the University of Kentucky COBRE Early Career Program (P20 GM103527) and the NIH Grant R01 HL124266. This work was also supported by grants from the Department of Veterans Affairs: CX001550BX001984 and CX001550 and NIH/NHLBI: HL120507 and NIGMS GM103527 to AJM and SSS.We are grateful for Jennifer Simkin for her assistance with the immunohistochemistry studies. We thank the University of Kentucky COBRE histology core for their assistance with the histological sections. The UK Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. This study used resources provided by the Lexington Veterans Affairs Medical Center. Publisher Copyright: {\textcopyright} 2020",

year = "2020",

month = dec,

doi = "10.1016/j.yjmcc.2020.09.011",

language = "English",

volume = "149",

pages = "95--114",

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Tripathi, H, Al-Darraji, A, Abo-Aly, M, Peng, H, Shokri, E, Chelvarajan, L, R. Donahue, R, Levitan, BM, Gao, E, Hernandez, G, Morris, AJ, Smyth, SS & Abdel-Latif, A 2020, 'Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction', Journal of Molecular and Cellular Cardiology, vol. 149, pp. 95-114. https://doi.org/10.1016/j.yjmcc.2020.09.011

TY - JOUR

T1 - Autotaxin inhibition reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction

AU - Tripathi, Himi

AU - Al-Darraji, Ahmed

AU - Abo-Aly, Mohamed

AU - Peng, Hsuan

AU - Shokri, Elica

AU - Chelvarajan, Lakshman

AU - R. Donahue, Renee

AU - Levitan, Bryana M.

AU - Gao, Erhe

AU - Hernandez, Gabriela

AU - Morris, Andrew J.

AU - Smyth, Susan S.

AU - Abdel-Latif, Ahmed

N1 - Funding Information: The UK Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant ( P30 CA177558 ) to the University of Kentucky Markey Cancer Center. This study used resources provided by the Lexington Veterans Affairs Medical Center. Funding Information: Dr. Abdel-Latif is supported by the University of Kentucky COBRE Early Career Program ( P20 GM103527 ) and the NIH Grant R01 HL124266 . This work was also supported by grants from the Department of Veterans Affairs : CX001550BX001984 and CX001550 and NIH/NHLBI : HL120507 and NIGMS GM103527 to AJM and SSS. Funding Information: Dr. Abdel-Latif is supported by the University of Kentucky COBRE Early Career Program (P20 GM103527) and the NIH Grant R01 HL124266. This work was also supported by grants from the Department of Veterans Affairs: CX001550BX001984 and CX001550 and NIH/NHLBI: HL120507 and NIGMS GM103527 to AJM and SSS.We are grateful for Jennifer Simkin for her assistance with the immunohistochemistry studies. We thank the University of Kentucky COBRE histology core for their assistance with the histological sections. The UK Flow Cytometry & Cell Sorting core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center and an NCI Center Core Support Grant (P30 CA177558) to the University of Kentucky Markey Cancer Center. This study used resources provided by the Lexington Veterans Affairs Medical Center. Publisher Copyright: © 2020

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

KW - Autotaxin

KW - Heart failure

KW - Inflammation

KW - Lysophosphatidic acid

KW - Myocardial infarction

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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