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

Abstract

BackgroundMatrix 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 ResultsMmp2−/− (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 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.ConclusionsA 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.

Identification of a Novel Heart–Liver Axis: Matrix Metalloproteinase‐2 Negatively Regulates Cardiac Secreted Phospholipase A 2 to Modulate Lipid Metabolism and Inflammation in the Liver

“…Recently, we reported an MMP‐2/cardiac sPLA 2 mechanism that modulates blood pressure homeostasis, cardiac inflammation, and lipopolysaccharide‐induced fever . We confirmed the heart as a major source of systemic sPLA 2 activity in Mmp2 −/ − mice (Figure A).…”

“…Dr Fernandez‐Patron's laboratory used the commercial assay kit (Cayman) with diheptanoyl thio‐phosphatidyl choline as substrate, per the manufacturer's instructions. Ex vivo tissue release of sPLA 2 activity was equally measured using the Cayman kit, as described earlier . Confirmatory studies and the extended characterization of cardiac sPLA 2 biochemical properties were conducted by Dr Lambeau's laboratory using the highly sensitive [ 3 H]‐oleic acid–radiolabeled Escherichia coli membrane assay.…”

“…The evident coexistence of inflammation and metabolic dysregulation with MMP‐2 deficiency is of potential clinical significance but is very poorly understood. In this study, we report that the hepatic metabolic phenotype in Mmp2 −/− mice can be largely explained by a novel heart–liver axis involving myocardial secretion of a unique phospholipase A 2 (PLA 2 ), which we coined cardiac secreted PLA 2 (sPLA 2 ) . Our findings identify a novel functional link between cardiac inflammation and hepatic metabolism.…”

“…Genetic loss of MMP‐2 ( Mmp2 −/− ) in mice results in an arthritis‐like phenotype associated with skeletal, bone, and craniofacial defects . In addition, Mmp2 −/− mice resist diet‐induced obesity during development, exhibit cardiac inflammation at baseline, and are predisposed to hypertensive heart disease due to abnormal regulation of the sterol regulatory binding protein 2 (SREBP‐2) pathway in the heart …”

Anti-CCL21 Antibody Attenuates Infarct Size and Improves Cardiac Remodeling After Myocardial Infarction

“…MMPs are important proteolytic enzymes that lead to degradation of the extracellular matrix and to changes in cardiomyocytes in both infarcted and non-infarcted myocardium [44]. Moreover, Matrix metalloproteinases (MMPs) have recently emerged as modulators of cardiovascular inflammation [45,46]. In addition to ECM, MMP substrates also include a multitude of cytokines, chemokines, growth factors, and adhesion molecules [47].…”