Matrix metalloproteinase-2 negatively regulates cardiac secreted phospholipase A2 to modulate inflammation and fever

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. methods and 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 ca2+-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 inhibitmmp-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. © 2015 the authors.