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

Abstract

BackgroundEndocrine functions of the heart have been well established. We investigated the hypothesis that cardiac secretion of a unique phospholipase A2 recently identified by our laboratory (cardiac secreted phospholipase A2 [sPLA 2]) establishes a heart–liver endocrine axis that is negatively regulated by matrix metalloproteinase‐2 (MMP‐2).Methods and ResultsIn Mmp2 −/− mice, cardiac (but not hepatic) sPLA 2 was elevated, leading to hepatic inflammation, immune cell infiltration, dysregulation of the sterol regulatory element binding protein‐2 and liver X receptor‐α pathways, abnormal transcriptional responses to dietary cholesterol, and elevated triglycerides in very low‐density lipoprotein and in the liver. Expression of monocyte chemoattractant protein‐3, a known MMP‐2 substrate, was elevated at both mRNA and protein levels in the heart. Functional studies including in vivo antibody neutralization identified cardiac monocyte chemoattractant protein 3 as a possible agonist of cardiac sPLA 2 secretion. Conversely, systemic sPLA 2 inhibition almost fully normalized the cardiohepatic phenotype without affecting monocyte chemoattractant protein‐3. Finally, wild‐type mice that received high‐performance liquid chromatography–isolated cardiac sPLA 2 from Mmp2 −/− donors developed a cardiohepatic gene expression profile similar to that of Mmp2 −/− mice.ConclusionsThese findings identified the novel MMP‐2/cardiac sPLA 2 pathway that endows the heart with important endocrine functions, including regulation of inflammation and lipid metabolism in the liver. Our findings could also help explain how MMP2 deficiency leads to cardiac problems, inflammation, and metabolic dysregulation in patients.

Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

“…We recently found that in Mmp2 −/− mice, the heart secretes an as yet unidentified PLA 2 (cardiac sPLA 2 ), which circulates in plasma, acting as a signal that is governed by MMP‐2 and that modulates lipid metabolism in the liver . In Mmp9 −/− mice, plasma sPLA 2 activity was significantly higher than in WT plasma but otherwise was normal in the heart, as demonstrated by assaying the generation of free thiol from di‐heptanoyl‐thio‐phosphatidylcholine (substrate) (Figure A).…”

“…Data are representative of technical duplicates. For comparison, the activity of cardiac sPLA 2 from an Mmp2 −/− mouse (mouse “E” in figure S3 of Hernandez‐Anzaldo et al) is presented. * P <0.05 vs Mmp2 −/− plasma, t test.…”

“…We recently discovered numerous differences in expression of lipid metabolic genes between WT and MMP‐2–deficient mice including an upregulation of genes in the SREBP‐2 pathway and impaired hepatic transcriptional responses to dietary cholesterol …”

“…We recently reported that the cardiohepatic metabolic phenotype in MMP ‐2–deficient ( Mmp2 −/− ) mice can be largely explained by a novel heart–liver axis involving myocardial secretion of a unique phospholipase A 2 (PLA 2 ) called cardiac secreted PLA 2 (sPLA 2 ) . Purportedly, the MMP‐2–cardiac sPLA 2 axis enables the heart to signal to the liver to satisfy its energy needs.…”

“…In addition, the MMP‐2–cardiac sPLA 2 system enhances the production of prostaglandin E 2 in the heart, brain, and liver. Consequently, a heart‐centric mechanism using cardiac sPLA 2 as a signal governed by MMP‐2 influences the metabolism of other noncardiac organs …”