Dhruva J Dwivedi1, Peter M Grin, Momina Khan, Annik Prat, Ji Zhou, Alison E Fox-Robichaud, Nabil G Seidah, Patricia C Liaw. 1. *Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada †Department of Medicine, McMaster University, Hamilton, Ontario, Canada ‡Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada §Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal (IRCM), University of Montréal, Montréal, Québec, Canada.
Abstract
INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets lipoprotein receptors for degradation, thereby reducing hepatic lipid clearance. PCSK9 inhibition reduces mortality in septic mice, presumably through increased hepatic clearance of pathogen lipids due to increased lipoprotein receptor concentrations. However, PCSK9 overexpression in vivo has not been studied in sepsis. Therefore, this study aimed to evaluate the effects of differential PCSK9 expression on systemic infection, inflammation, and coagulation in sepsis. METHODS: Wild-type, PCSK9 knockout (KO), and transgenic (Tg) mice that overexpress PCSK9 were subjected to sham surgery or cecal ligation and puncture (CLP). Bacterial loads were measured in lungs, peritoneal cavity fluid, and blood. Organ pathology was assessed in lungs, liver, and kidneys. Lung myeloperoxidase activity, and plasma concentrations of alanine aminotransferase (ALT), creatinine, cell-free DNA (cfDNA), protein C, thrombin-antithrombin (TAT) complexes, interleukin (IL)-6, and IL-10 were also measured 6 h postoperatively. Morbidity was assessed for 16 h following CLP. RESULTS: Overexpression of PCSK9 in mice increased liver and kidney pathology, plasma IL-6, ALT, and TAT concentrations during sepsis, whereas PCSK9 KO mice exhibited reduced bacterial loads, lung and liver pathology, myeloperoxidase activity, plasma IL-10, and cfDNA during CLP-induced sepsis. All septic mice had reduced plasma levels of protein C, but the protein C ratio relative to normal was significantly decreased in PCSK9 Tg mice. Dyspnea, cyanosis, and overall grimace scores were greatest in septic mice overexpressing PCSK9, whereas PCSK9 KO mice retained core body temperature during sepsis. CONCLUSION: These findings demonstrate that PCSK9 deficiency confers protection against systemic bacterial dissemination, organ pathology, and tissue inflammation, particularly in the lungs and liver, while PCSK9 overexpression exacerbates multi-organ pathology as well as the hypercoagulable and pro-inflammatory states in early sepsis.
INTRODUCTION:Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets lipoprotein receptors for degradation, thereby reducing hepatic lipid clearance. PCSK9 inhibition reduces mortality in septic mice, presumably through increased hepatic clearance of pathogen lipids due to increased lipoprotein receptor concentrations. However, PCSK9 overexpression in vivo has not been studied in sepsis. Therefore, this study aimed to evaluate the effects of differential PCSK9 expression on systemic infection, inflammation, and coagulation in sepsis. METHODS: Wild-type, PCSK9 knockout (KO), and transgenic (Tg) mice that overexpress PCSK9 were subjected to sham surgery or cecal ligation and puncture (CLP). Bacterial loads were measured in lungs, peritoneal cavity fluid, and blood. Organ pathology was assessed in lungs, liver, and kidneys. Lung myeloperoxidase activity, and plasma concentrations of alanine aminotransferase (ALT), creatinine, cell-free DNA (cfDNA), protein C, thrombin-antithrombin (TAT) complexes, interleukin (IL)-6, and IL-10 were also measured 6 h postoperatively. Morbidity was assessed for 16 h following CLP. RESULTS: Overexpression of PCSK9 in mice increased liver and kidney pathology, plasma IL-6, ALT, and TAT concentrations during sepsis, whereas PCSK9 KO mice exhibited reduced bacterial loads, lung and liver pathology, myeloperoxidase activity, plasma IL-10, and cfDNA during CLP-induced sepsis. All septic mice had reduced plasma levels of protein C, but the protein C ratio relative to normal was significantly decreased in PCSK9 Tg mice. Dyspnea, cyanosis, and overall grimace scores were greatest in septic mice overexpressing PCSK9, whereas PCSK9 KO mice retained core body temperature during sepsis. CONCLUSION: These findings demonstrate that PCSK9 deficiency confers protection against systemic bacterial dissemination, organ pathology, and tissue inflammation, particularly in the lungs and liver, while PCSK9 overexpression exacerbates multi-organ pathology as well as the hypercoagulable and pro-inflammatory states in early sepsis.
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