title: Matrix metalloproteinase-2 negatively regulates cardiac secreted phospholipase A2 to modulate inflammation and fever.
abstract: BACKGROUND
  Matrix metalloproteinase (MMP)-2 deficiency makes humans and mice susceptible to inflammation. Here, we reveal an MMP-2-mediated mechanism that modulates the inflammatory response via secretory phospholipase A2 (sPLA2), a phospholipid hydrolase that releases fatty acids, including precursors of eicosanoids.
  
  
  RESULTS
  Mmp2(-/-) (and, to a lesser extent, Mmp7(-/-) and Mmp9(-/-)) mice had between 10- and 1000-fold elevated sPLA2 activity in plasma and heart, increased eicosanoids and inflammatory markers (both in the liver and heart), and exacerbated lipopolysaccharide-induced fever, all of which were blunted by adenovirus-mediated MMP-2 overexpression and varespladib (pharmacological sPLA2 inhibitor). Moreover, Mmp2 deficiency caused sPLA2-mediated dysregulation of cardiac lipid metabolic gene expression. Compared with liver, kidney, and skeletal muscle, the heart was the single major source of the Ca(2+)-dependent, ≈20-kDa, varespladib-inhibitable sPLA2 that circulates when MMP-2 is deficient. PLA2G5, which is a major cardiac sPLA2 isoform, was proinflammatory when Mmp2 was deficient. Treatment of wild-type (Mmp2(+/+)) mice with doxycycline (to inhibit MMP-2) recapitulated the Mmp2(-/-) phenotype of increased cardiac sPLA2 activity, prostaglandin E2 levels, and inflammatory gene expression. Treatment with either indomethacin (to inhibit cyclooxygenase-dependent eicosanoid production) or varespladib (which inhibited eicosanoid production) triggered acute hypertension in Mmp2(-/-) mice, revealing their reliance on eicosanoids for blood pressure homeostasis.
  
  
  CONCLUSIONS
  A heart-centric MMP-2/sPLA2 axis may modulate blood pressure homeostasis, inflammatory and metabolic gene expression, and the severity of fever. This discovery helps researchers to understand the cardiovascular and systemic effects of MMP-2 inhibitors and suggests a disease mechanism for human MMP-2 gene deficiency.
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (E.B., S.H.A., X.W., C.F.P.).
authors.forename: Evan
authors.initials: E
authors.lastname: Berry
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (E.B., S.H.A., X.W., C.F.P.).
authors.forename: Samuel
authors.initials: S
authors.lastname: Hernandez-Anzaldo
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA (F.G., M.H.G.).
authors.forename: Farideh
authors.initials: F
authors.lastname: Ghomashchi
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: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan (M.M.) CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan (M.M.).
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA (F.G., M.H.G.).
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
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: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (E.B., S.H.A., X.W., C.F.P.).
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada (E.B., S.H.A., X.W., 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: D000818:Animals; D002460:Cell Line; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D015232:Dinoprostone / Q000032:analysis; D005334:Fever / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000737:chemistry; D054497:Phospholipases A2, Secretory / Q000032:analysis / Q000097:blood / Q000502:physiology*; D016133:Polymerase Chain Reaction
chemical_list: C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D054497:Phospholipases A2, Secretory; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D015232:Dinoprostone
keywords: PLA2; heart; inflammation; matrix metalloproteinases
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