Matrix Metalloproteinase‐2 Negatively Regulates Cardiac Secreted Phospholipase A(2) to Modulate Inflammation and Fever

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 A(2) (sPLA(2)), 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 sPLA(2) 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 sPLA(2) inhibitor). Moreover, Mmp2 deficiency caused sPLA(2)‐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 sPLA(2) that circulates when MMP‐2 is deficient. PLA2G5, which is a major cardiac sPLA(2) 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 sPLA(2) activity, prostaglandin E(2) 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/sPLA(2) 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.