Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE-/- mice.

The family of secretory phospholipase A2 (sPLA2) enzymes has been associated with inflammatory diseases and tissue injury including atherosclerosis. A-001 is a novel inhibitor of sPLA2 enzymes discovered by structure-based drug design, and A-002 is the orally bioavailable prodrug currently in clinical development. A-001 inhibited human and mouse sPLA2 group IIA, V, and X enzymes with IC50 values in the low nM range.

Circulating Markers Reflect Both Anti- and Pro-Atherogenic Drug Effects in ApoE-Deficient Mice.

BACKGROUND: Current drug therapy of atherosclerosis is focused on treatment of major risk factors, e.g. hypercholesterolemia while in the future direct disease modification might provide additional benefits.

Transgenic mice with cardiac-specific over-expression of MLK7 have increased mortality when exposed to chronic beta-adrenergic stimulation.

Mixed lineage kinase 7 (MLK7) is a recently identified mitogen-activated protein kinase kinase kinase with enriched expression in skeletal muscle and heart. When over-expressed in cardiac myocytes, MLK7 activates both the p38 and c-Jun N-terminal kinase (JNK) stress-activated pathways and induces a cellular phenotype characteristic of cardiac hypertrophy, including a fetal gene expression pattern and increased protein synthesis. We sought to determine the effect of MLK7 on cardiac function in vivo by generating transgenic (Tg) mice with cardiac restricted over-expression of the enzyme.

Heart failure and greater infarct expansion in middle-aged mice: a relevant model for postinfarction failure.

Young mice tolerate myocardial loss after coronary artery ligation (CAL) without congestive heart failure (CHF) signs or mortality. We predicted a CHF phenotype after CAL in aged mice. Left coronary artery ligation produced permanent myocardial infarcts (MI).