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

Background Endocrine functions of the heart have been well established. We investigated the hypothesis that cardiac secretion of a unique phospholipase A 2 recently identified by our laboratory (cardiac secreted phospholipase A 2 [ sPLA 2 ]) establishes a heart–liver endocrine axis that is negatively regulated by matrix metalloproteinase‐2 (MMP‐2). Methods and Results In 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 h igh‐performance liquid chromatography –isolated cardiac sPLA 2 from Mmp2 −/− donors developed a cardiohepatic gene expression profile similar to that of Mmp2 −/− mice. Conclusions These 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 MMP 2 deficiency leads to cardiac problems, inflammation, and metabolic dysregulation in patients.