Potential therapeutic targets and citrullination by PAD4 after MI. (A) Activated endothelium releases VWF that binds circulating platelets and leukocytes and promotes thrombosis and inflammation after acute MI. ADAMTS13 cleaves VWF and inhibits platelet aggregation and early leukocyte recruitment and NET formation. NETs released from activated neutrophils or dying cardiomyocytes are prothrombotic by trapping platelets and red blood cells, and binding tissue factor. DNase I, which degrades NETs, is protective against cardiac injury. (B) PAD4 catalyzes imine to ketone reactions in a Ca²⁺-dependent manner on specific peptidyl arginine side groups of nuclear proteins, such as histones H3 and H4, a process known as citrullination or deimination. This process is required for the NET formation. Inactivation of PAD4 enzymatic activity genetically or pharmacologically inhibits thrombosis and inflammatory response and may be protective against cardiac damage after acute MI. ECs, endothelial cells; RBC, red blood cell; TF, tissue factor.