title: Identification of a Novel Heart-Liver Axis: Matrix Metalloproteinase-2 Negatively Regulates Cardiac Secreted Phospholipase A2 to Modulate Lipid Metabolism and Inflammation in the Liver.
abstract: BACKGROUND
  Endocrine functions of the heart have been well established. We investigated the hypothesis that cardiac secretion of a unique phospholipase A2 recently identified by our laboratory (cardiac secreted phospholipase A2 [sPLA2]) establishes a heart-liver endocrine axis that is negatively regulated by matrix metalloproteinase-2 (MMP-2).
  
  
  RESULTS
  In Mmp2(-/-) mice, cardiac (but not hepatic) sPLA2 was elevated, leading to hepatic inflammation, immune cell infiltration, dysregulation of the sterol regulatory element binding protein-2 and liver X receptor-α pathways, abnormal transcriptional responses to dietary cholesterol, and elevated triglycerides in very low-density lipoprotein and in the liver. Expression of monocyte chemoattractant protein-3, a known MMP-2 substrate, was elevated at both mRNA and protein levels in the heart. Functional studies including in vivo antibody neutralization identified cardiac monocyte chemoattractant protein 3 as a possible agonist of cardiac sPLA2 secretion. Conversely, systemic sPLA2 inhibition almost fully normalized the cardiohepatic phenotype without affecting monocyte chemoattractant protein-3. Finally, wild-type mice that received high-performance liquid chromatography-isolated cardiac sPLA2 from Mmp2(-/-) donors developed a cardiohepatic gene expression profile similar to that of Mmp2(-/-) mice.
  
  
  CONCLUSIONS
  These findings identified the novel MMP-2/cardiac sPLA2 pathway that endows the heart with important endocrine functions, including regulation of inflammation and lipid metabolism in the liver. Our findings could also help explain how MMP2 deficiency leads to cardiac problems, inflammation, and metabolic dysregulation in patients.
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (S.H.A., E.B., D.L., C.F.P.).
authors.forename: Samuel
authors.initials: S
authors.lastname: Hernandez-Anzaldo
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (S.H.A., E.B., D.L., C.F.P.).
authors.forename: Evan
authors.initials: E
authors.lastname: Berry
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice-Sophia Antipolis, Valbonne, France (V.B., L.).
authors.forename: Vesna
authors.initials: V
authors.lastname: Brglez
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (S.H.A., E.B., D.L., C.F.P.).
authors.forename: Dickson
authors.initials: D
authors.lastname: Leung
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada (T.J.Y., J.S.L., C.C.) Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada (T.J.Y.).
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Yun
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada (T.J.Y., J.S.L., C.C.) Department of Microbiology and Immunology, University of Montreal, Quebec, Canada (J.S.L., C.C.).
authors.forename: Jun Seong
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Innate Immunity System (Inflammation) and Vascular Immunology, The Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Quebec, Canada (J.G.F.).
authors.forename: Janos G
authors.initials: JG
authors.lastname: Filep
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Z.K.) Cardiovascular Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Z.K., C.F.P.) Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Z.K., C.F.P.).
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada (T.J.Y., J.S.L., C.C.) Department of Microbiology and Immunology, University of Montreal, Quebec, Canada (J.S.L., C.C.).
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Nice-Sophia Antipolis, Valbonne, France (V.B., L.).
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.affiliation: Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (R.L.) Group on Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (R.L.).
authors.forename: Richard
authors.initials: R
authors.lastname: Lehner
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (S.H.A., E.B., D.L., C.F.P.) Cardiovascular Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Z.K., C.F.P.) Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (Z.K., C.F.P.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Patron
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D054410:Chemokine CCL7 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006505:Hepatitis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D007211:Indoles / Q000494:pharmacology; D007651:Keto Acids; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D010641:Phenotype; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000085:Acetates; D000906:Antibodies; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D007211:Indoles; D007651:Keto Acids; D014280:Triglycerides; C117948:varespladib; D054497:Phospholipases A2, Secretory; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: heart; inflammation; liver; matrix metalloproteinase; metabolism; phospholipase A2