Mechanisms of PCSK9 in endothelial aging

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PROJECT SUMMARY/ABSTRACT Cardiovascular and cerebrovascular diseases are the leading cause of global deaths contributing to as much as one third of deaths, according to the World Health Organization's Global Status Report on Noncommunicable Diseases. Endothelial cell senescence and subsequent endothelial aging are closely associated with cardiovascular and cerebrovascular diseases in older people. PCSK9 is a serine protease that plays an important role in regulating inflammatory responses and programmed cell death. We recently reported that PCSK9 contributes to mitochondrial DNA damage, NLRP3 inflammasome activation, and pyroptosis (an inflammatory form of programmed cell death), leading to the release of pro-inflammatory cytokines IL-1β and IL-18. In addition, we found that MerTK, a marker for efferocytosis, is highly expressed in young endothelial cells while inhibited in old endothelial cells; efferocytosis is an important process by which apoptotic cells are removed by phagocytes. Based on our preliminary studies, the central hypothesis to be tested in this project is that aging-mediated PCSK9 upregulation impairs efferocytosis showing failed clearance of apoptotic cells, induces pyroptosis, and contributes to endothelial cell senescence and subsequent endothelial aging. Our long-term goal is to dissect the relationship between PCSK9, impaired efferocytosis, upregulated pyroptosis, and its role in the development of endothelial aging. Our specific aims are: Aim 1 - Determine the contribution of endothelial cell-secreted PCSK9 to endothelial aging; Aim 2 - Define the role of PCSK9 in regulating efferocytosis; and Aim 3 - Define the role of PCSK9 in regulating pyroptosis. The proposed research is innovative because it will connect PCSK9 with impaired efferocytosis and upregulated pyroptosis in endothelial cells and evaluate the contribution of endothelial cell-secreted PCSK9 to endothelial aging. Insight into the novel mechanism of mitochondrial DNA damage may identify novel ideas for drugs designed to control impaired efferocytosis, targeted at mtDNA damage.