Abstract 12983: mtDNA Damage in Concert With PCSK9 Expression Induces Apoptosis in Vascular Smooth Muscle Cells

Abstract

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in inducing hypercholesterolemia and associated cardiovascular diseases. Autophagy is considered a protective and adaptive mechanism to promote cell survival, while apoptosis represents cell death program designed to remove injured cells. Exposure of vascular smooth muscle cells (SMCs) to noxious stimuli such as LPS or ox-LDL induces PCSK9 expression and apoptosis. Methods and Results: Treatment of human primary vascular SMCs to 20 ng/ml LPS significantly induced both mtDNA damage and PCSK9 expression. mtDNA damage induction with the autophagy inhibitor 3-methyladenine enhanced PCSK9 expression, whereas mtDNA damage inhibition with the autophagy inducer rapamycin reduced PCSK9 expression, indicating an interplay between autophagy, mtDNA damage and PCSK9. Inhibition of DNase II (siRNA) for reduced the extent of mtDNA damage and PCSK9 expression confirmed the role of mtDNA damage in PCSK9 expression. Next, we investigated the role of PCSK9 in the development of apoptosis. We observed that PCSK9 upregulation by hPCSK9 treatment induced and PCSK9 inhibition by siRNA transfection reduced apoptosis of SMCs (measured as TUNEL staining and expression of Bax, Bcl2 and cleaved caspase-3). Conclusions: These observations provide a compelling evidence for the role of mtDNA damage in PCSK9 release. Both collectively induce SMC apoptosis during inflammatory states characteristic of cardiovascular diseases, such as atherosclerosis.