2 Interestingly, humans with genetic loss of MMP‐2 activity suffer from crippling arthritis 4, 5, 6 and a spectrum of cardiovascular problems including congenital cardiac malformations, transposition of the great arteries, mitral valve prolapse, bicuspid aortic valve, and atrial and ventricular septal defects. MCP‐3 is also reported to be a physiological substrate of MMP‐2 in arthritis. The resultant MCP‐3 peptide serves as a general antagonist of CC‐chemokine receptors that inhibits inflammation signaling by intact MCP‐3 and other chemokine receptor ligands. Binding of the hemopexin domain of MMP‐2 to MCP‐3 facilitates cleavage of MCP‐3 at a glycine/isoleucine bond. 2, 3 MCP‐3 is a CC‐motif (N‐terminus has 2 consecutive conserved cysteine residues) chemokine that is 76 amino acids long. 1Īmong the cytokines targeted by MMP‐2 is monocyte chemoattractant protein‐3 (MCP‐3 encoded by Ccl7).

A spectrum of cellular processes covering cellular proliferation, angiogenesis, and inflammation is modulated through MMP‐2–dependent cleavage and regulation of extracellular matrix components, cell membrane receptors, latent growth factors, and cytokines. Matrix metalloproteinase‐2 (MMP‐2), sometimes referred to as gelatinase A or 72 kDa collagenase, is a member of a family comprising 25 different Zn‐dependent endoproteases. 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. Conversely, systemic sPLA 2 inhibition almost fully normalized the cardiohepatic phenotype without affecting monocyte chemoattractant protein‐3. Functional studies including in vivo antibody neutralization identified cardiac monocyte chemoattractant protein 3 as a possible agonist of cardiac sPLA 2 secretion. Expression of monocyte chemoattractant protein‐3, a known MMP‐2 substrate, was elevated at both mRNA and protein levels in the heart. 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.

Journal of the American Heart Association (JAHA).

Stroke: Vascular and Interventional Neurology.

Circ: Cardiovascular Quality & Outcomes.

Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).

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