Key result
MMP-2 deficiency in mice led to 10- to 1000-fold elevated sPLA2 activity, increased inflammatory markers, and exacerbated fever, which were blunted by MMP-2 overexpression or sPLA2 inhibition.
MMP-2 negatively regulates cardiac sPLA2, and its deficiency leads to increased inflammation, fever, and reliance on eicosanoids for blood pressure homeostasis.
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Invites human validation of MMP-2–sPLA2 inflammation axis; leaves open any therapeutic relevance in cardiovascular disease.
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. 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 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.
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Berry et al. (2015) studied Inflammation and fever. MMP-2 deficiency vs. Wild-type (Mmp2(+/+)) mice was evaluated on sPLA2 activity, eicosanoids, inflammatory markers, and fever. MMP-2 deficiency in mice led to 10- to 1000-fold elevated sPLA2 activity, increased inflammatory markers, and exacerbated fever, which were blunted by MMP-2 overexpression or sPLA2 inhibition.
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