1. Date of download: 7/9/2016 From: Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: A Narrative Review Ann Intern Med. 2016;164(9):600-607. doi:10.7326/M15-2994 Several adverse mechanisms on coronary plaque by PCSK9. ACS = acute coronary syndrome; LDL = low-density lipoprotein; MMP = matrix metalloproteinase; NF-κB = nuclear factor-κB; PCSK9 = proprotein convertase subtilisin/kexin type 9. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

2. Date of download: 7/9/2016 From: Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: A Narrative Review Ann Intern Med. 2016;164(9):600-607. doi:10.7326/M15-2994 Time pattern of change of PCSK9 levels from experimental studies. AMI = acute myocardial infarction; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; PCSK9 = proprotein convertase subtilisin/kexin type 9. * Evidence from animal studies. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

3. Date of download: 7/9/2016 From: Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: A Narrative Review Ann Intern Med. 2016;164(9):600-607. doi:10.7326/M15-2994 Potential antiplatelet effects of PCSK9 antibodies. Native LDL binds to the ApoER2 and activates cPLA 2 through the p38 MAPK pathway. cPLA 2 releases AA from membrane phospholipids that is converted to prostaglandin H 2 by the COX-1 enzyme and subsequently to TxA 2 by Tx synthase. TxA 2 acts synergistically with downstream signaling generated by the binding of platelet agonists (ADP, collagen, and thrombin) to respective receptors to activate GPIIb/IIIa receptors. Activated GPIIb/IIIa receptors from adjacent platelets bind to fibrinogen, which causes platelet aggregation and thrombosis at the site of plaque rupture. Similarly, oxLDL binds to scavenger receptors (CD36 and SRA) and activates p38 MAPK. PCSK9 antibodies prevent LDL receptor degradation and thereby enhance LDL cholesterol clearance from the circulation. The latter effect decreases the platelet activation and aggregation induced by native LDL and oxLDL. AA = arachidonic acid; ACS = acute coronary syndrome; ADP = adenosine diphosphate; ApoER2 = apolipoprotein E receptor-2; COX-1 = cyclooxygenase-1; cPLA 2 = cytosolic phospholipase A 2 ; GPIIb/IIIa = glycoprotein IIb/IIIa; LDL = low-density lipoprotein; mLPA = membrane phospholipids; oxLDL = oxidized low-density lipoprotein; p38 MAPK = p38 mitogen-activated protein kinase ; PCSK9 = proprotein convertase subtilisin/kexin type 9; SRA = scavenger receptor A; Tx = thromboxane; TxA 2 = thromboxane A 2. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians