Identification of a Novel Heart–Liver Axis: Matrix Metalloproteinase‐2 Negatively Regulates Cardiac Secreted Phospholipase A2 to Modulate Lipid Metabolism and Inflammation in the Liver

Autor: Tae Jin Yun, János G. Filep, Cheolho Cheong, Vesna Brglez, Samuel Hernandez-Anzaldo, Zamaneh Kassiri, Dickson Leung, Richard Lehner, Evan Berry, Carlos Fernandez-Patron, Jun Seong Lee, Gérard Lambeau
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Indoles
Time Factors
Transcription
Genetic
030204 cardiovascular system & hematology
Acetates
Hepatitis
Cholesterol
Dietary
0302 clinical medicine
Medicine
Myocytes
Cardiac
Chemokine CCL7
Enzyme Inhibitors
Cells
Cultured
Original Research
Regulation of gene expression
Mice
Knockout
0303 health sciences
biology
Keto Acids
3. Good health
medicine.anatomical_structure
Phenotype
Matrix Metalloproteinase 2
Signal transduction
medicine.symptom
Cardiology and Cardiovascular Medicine
Signal Transduction
medicine.medical_specialty
matrix metalloproteinase
Inflammation
heart
liver
Antibodies
03 medical and health sciences
Phospholipase A2
Internal medicine
Animals
Secretion
Genetic Predisposition to Disease
Liver X receptor
Phospholipases A2
Secretory
Triglycerides
030304 developmental biology
business.industry
Monocyte
Lipid metabolism
Lipid Metabolism
Mice
Inbred C57BL
Endocrinology
Gene Expression Regulation
inflammation
biology.protein
phospholipase A2
business
metabolism
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: 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.
Databáze: OpenAIRE
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