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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.

journal of the american heart association

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