The underlying pathological process of coronary artery disease (CAD) is the development of coronary artery atherosclerotic occlusions and associated myocardial infarction. Both increased chronic inflammation and plasma low-density lipoprotein (LDL) cholesterol levels promote atherosclerosis. Inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) is widely known for its role in enhancing LDL receptor (LDLR)-mediated cholesterol lowering when the LDLR-apolipoprotein E (APOE) axis is intact and protecting against atherosclerosis progression by reducing plasma cholesterol levels. In this thesis, we sought to test the effects of PCSK9 inhibition mediated cholesterol lowering on pre-existing CAD as well as the plasma cholesterol independent effects of PCSK9 inhibition on CAD by utilizing different mouse models. One year old scavenger receptor class B type I (Sr-b1) knockout (KO) mice which have an intact LDLR-APOE axis, develop coronary artery atherosclerosis and myocardial fibrosis induced by a high fat, high cholesterol and cholate containing (HFCC) diet. Weekly anti-PCSK9 antibody treatment initiated one week before switching to an HFCC diet increased hepatic LDLR protein levels, and reduced plasma cholesterol levels and the progression of atherosclerosis in both the aortic sinus and coronary arteries in one year old Sr-b1 KO mice (maintained on an HFCC diet for 7 weeks). Weekly anti-PCSK9 antibody treatment initiated 7 weeks after switching to an HFCC diet also increased hepatic LDLR protein levels and reduced plasma cholesterol levels in one year old Sr-b1 KO mice (maintained on an HFCC diet for 12 weeks). More importantly, anti-PCSK9 antibody treatment during the last 5 weeks of the 12-week HFCC diet feeding period also slowed down the growth of pre-existing atherosclerosis in both the aortic sinus and coronary arteries and reduced myocardial fibrosis and damage. Mice deficient in both Sr-b1 and ApoE (Sr-b1/ApoE double KO (dKO) mice) spontaneously and rapidly develop features reminiscent of human CAD. Whole body Pcsk9 genetic KO in both female and male Sr-b1/ApoE dKO mice did not affect plasma cholesterol levels despite increased hepatic LDLR protein levels, presumably due to the lack of APOE. However, genetic Pcsk9 inactivation significantly attenuated atherosclerosis in both the aortic sinus and coronary arteries, myocardial fibrosis and damage, left ventricle (LV) dysfunction and cardiac enlargement in both female and male Sr-b1/ApoE dKO mice. Restoring circulating PCSK9 by a recombinant adeno associated virus 8 (AAV8)-mediated hepatic expression of a Pcsk9 cDNA in Pcsk9/Sr-b1/ApoE triple KO mice reversed the plasma cholesterol independent protective effects of genetic PCSK9 KO on aortic sinus and coronary artery atherosclerosis and myocardial fibrosis and damage in both females and males. Treatment of Sr-b1/ApoE dKO mice with an anti-PCSK9 antibody which disrupts the interaction between the LDLR and PCSK9 protected against aortic sinus and coronary artery atherosclerosis in males but not in females and did not protect either males or females against myocardial fibrosis and damage, LV dysfunction or cardiac enlargement. My thesis demonstrates that anti-PCSK9 antibody mediated plasma cholesterol lowering delays the continued development of pre-existing CAD. My thesis also demonstrates that liver-derived, circulating PCSK9 promotes CAD in a plasma cholesterol independent manner in Sr-b1/ApoE dKO mice and these effects appear to be largely independent of the PCSK9-LDLR interaction, particularly in females. / Thesis / Doctor of Philosophy (PhD)

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