Kupffer Cells Mediate Platelet Aggregation Responses

Cardiovascular diseases (CVDs) are currently recognized as being the underlying pathology in approximately one‐third of deaths in the United States. Platelets are widely recognized as playing an important role in the pathogenesis of many CVDs by responding to various different biochemical and biomechanical factors. These factors are capable of influencing platelet activation and aggregation behaviors. Some of these factors can be secreted by cells such as endothelial cells and leukocytes, typically in response to trauma, contamination, or stress. Kupffer cells are liver‐resident macrophages that line the sinusoids of the liver and play an instrumental role in bacterial defense and phagocytosis, as well as in the processing of other toxins delivered to the liver from the gut. Although the liver receives a large percentage of the systemic blood, the response of Kupffer cells to traditional cardiovascular risk factors were largely unknown. Our group investigated the cytokine profile and release of reactive oxygen species from Kupffer cells upon exposure to known cardiovascular risk factors. This work indicated that Kupffer cells released a suite of factors known to affect platelet function. Thus, we hypothesized that exposure of platelets to Kupffer cell secretions resulting from exposure to cardiovascular risk factors would significantly increase platelet activation, adhesion, and aggregation response, promoting vascular disease processes. The objective of this study was to elucidate that effect of Kupffer cell secretions on platelet functions associated with CVD progression. To test this hypothesis, Kupffer cells were exposed to one of our selected known cardiovascular risk factors (e.g. tobacco smoke, advanced glycation end products, nicotine, altered lipid profiles) for 48 hours. Conditioned cell media was collected and stored for use with platelets. Using light transmission aggregometry, changes in the turbidity of platelet‐rich plasma exposed to various Kupffer cell conditioned media, for up to 4 hours, were observed. Thrombin receptor activating peptide was used as the agonist to precipitate aggregation responses. Platelet aggregation rate and percent of platelets participating in aggregation, as compared with control samples, were calculated using a customized code. Our results indicate that after exposure to Kupffer cell conditioned media platelet aggregation rate and percentage of platelets participating in aggregation increased across all conditions for all time points, relative to the control sample. This indicates a direct capacity for Kupffer cell secretions, arising from exposure to traditional cardiovascular risk factors, to alter platelet aggregation function. Further, this illustrates that more platelets participate in aggregation at an enhanced rate. Combined this suggests that Kupffer cells inflammatory responses may serve as an additional, potentially significant, source for alterations in platelet behavior during CVD processes. The relevance of this alternative pathway for platelet functional changes needs to be investigated so that better therapeutics can be developed to mitigate disease processes. Future work will elucidate the specific mechanisms of platelet activation or aggregation affected by Kupffer cell secretions. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .